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Wu H, Zhang Z, Xue Y, Guo J, Ouyang Z, Cao Z, Guo W, Zhang Q, Wang M, Gu X. PCSK9 Targeted Autophagosome-Tethering Compounds: Design, Synthesis, and Antiatherosclerosis Evaluation. J Med Chem 2025; 68:8190-8207. [PMID: 40226893 DOI: 10.1021/acs.jmedchem.4c02915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/15/2025]
Abstract
Atherosclerosis is a multifaceted disease involving various cell types and complex mechanisms, and it is the main cause of cardiovascular disease. Proprotein convertase subtilisin/kexin type-9 (PCSK9) has been identified as an effective target for treating atherosclerosis; however, most current research focuses on biological drugs. Our work optimized the previously reported autophagosome-tethering compound OY3, and specifically, compound W6 induced PCSK9 degradation with a 5-fold increase in activity and a 6-fold increase in bioavailability. Compared to the currently marketed PCSK9 drug, siRNA, W6 demonstrated comparable antiatherosclerosis effects both in vivo and in vitro. W6 exhibited beneficial effects on hepatocytes, endothelial cells, macrophages, and vascular smooth muscle cells involved in the atherosclerosis process, making it a promising potential antiatherosclerosis drug. This work highlights the feasibility of ATTECs in degrading both intracellular and extracellular proteins, and our novel PCSK9-ATTEC W6 provides a valuable reference for the treatment of atherosclerotic diseases.
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Affiliation(s)
- Hongyu Wu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201301, China
| | - Ziwen Zhang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201301, China
| | - Yongxing Xue
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201301, China
| | - Jiannan Guo
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201301, China
| | - Zhirong Ouyang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201301, China
| | - Zhonglian Cao
- Department of Biopharmaceuticals, School of Pharmacy, Fudan University, Shanghai 201301, China
| | - Wei Guo
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201301, China
| | - Qingwen Zhang
- State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai 201301, China
| | - Mo Wang
- Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
| | - Xianfeng Gu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201301, China
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Tan D, Yang X, Yang J, Fan G, Xiong G. PCSK9 in Vascular Aging and Age-Related Diseases. Aging Dis 2025:AD.2024.1713. [PMID: 40354375 DOI: 10.14336/ad.2024.1713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 02/27/2025] [Indexed: 05/14/2025] Open
Abstract
The aging process significantly contributes to human disease, and as worldwide life expectancy increases, addressing the challenges of aging and age-related cardiovascular diseases is becoming increasingly urgent. Vascular aging is a key link between aging and the development of age-related diseases. Recent studies indicate that proprotein convertase subtilisin/kexin type 9 (PCSK9), a type of protein involved in the metabolism of lipids, is crucial in modulating vascular aging by affecting the physiological functioning of vascular cells. PCSK9 is linked to lipid metabolism and chronic inflammation and is involved in regulating senescence-related activities, including migration, proliferation, apoptosis, and differentiation. These factors contribute to the aging of vascular cells and age-related vascular diseases, including atherosclerosis, hypertension, coronary artery disease, and cerebrovascular diseases. Given its involvement in these processes, this article provides a comprehensive summary of PCSK9's regulatory functions in vascular aging, highlighting potential therapeutic targets for combating age-related cardiovascular diseases.
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Affiliation(s)
- Dong Tan
- Department of Vascular Surgery, the Second Affiliated Hospital of University of South China, Hengyang, Hunan, China
- Pan-Vascular Research Group, Shenzhen University Affiliated Sixth Hospital, Shenzhen, Guangdong, China
| | - Xin Yang
- Pan-Vascular Research Group, Shenzhen University Affiliated Sixth Hospital, Shenzhen, Guangdong, China
- Department of Metabolism and Endocrinology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jing Yang
- Pan-Vascular Research Group, Shenzhen University Affiliated Sixth Hospital, Shenzhen, Guangdong, China
- Department of Metabolism and Endocrinology, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Gang Fan
- Pan-Vascular Research Group, Shenzhen University Affiliated Sixth Hospital, Shenzhen, Guangdong, China
- Department of Urology, Shenzhen University Affiliated Sixth Hospital, Shenzhen, Guangdong Province, China
| | - Guozuo Xiong
- Department of Vascular Surgery, the Second Affiliated Hospital of University of South China, Hengyang, Hunan, China
- Hunan Province Thrombotic Disease Prevention and Treatment Clinical Medical Research Center, The Third Affiliated Hospital of University of South China, Hengyang, Hunan, China
- Hunan Province Thrombotic Disease Prevention and Treatment Clinical Medical Research Center, The Second Affiliated Hospital of University of South China, Hengyang, Hunan, China
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3
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Testa G, Giannelli S, Staurenghi E, Cecci R, Floro L, Gamba P, Sottero B, Leonarduzzi G. The Emerging Role of PCSK9 in the Pathogenesis of Alzheimer's Disease: A Possible Target for the Disease Treatment. Int J Mol Sci 2024; 25:13637. [PMID: 39769398 PMCID: PMC11727734 DOI: 10.3390/ijms252413637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/13/2024] [Accepted: 12/17/2024] [Indexed: 01/12/2025] Open
Abstract
Alzheimer's disease (AD) is a multifactorial neurodegenerative disease mainly caused by β-amyloid (Aβ) accumulation in the brain. Among the several factors that may concur to AD development, elevated cholesterol levels and brain cholesterol dyshomeostasis have been recognized to play a relevant role. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein primarily known to regulate plasma low-density lipoproteins (LDLs) rich in cholesterol and to be one of the main causes of familial hypercholesterolemia. In addition to that, PCSK9 is also recognized to carry out diverse important activities in the brain, including control of neuronal differentiation, apoptosis, and, importantly, LDL receptors functionality. Moreover, PCSK9 appeared to be directly involved in some of the principal processes responsible for AD development, such as inflammation, oxidative stress, and Aβ deposition. On these bases, PCSK9 management might represent a promising approach for AD treatment. The purpose of this review is to elucidate the role of PCSK9, whether or not cholesterol-related, in AD pathogenesis and to give an updated overview of the most innovative therapeutic strategies developed so far to counteract the pleiotropic activities of both humoral and brain PCSK9, focusing in particular on their potentiality for AD management.
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Affiliation(s)
- Gabriella Testa
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, 10043 Orbassano, Italy; (G.T.); (S.G.); (E.S.); (R.C.); (L.F.); (P.G.); (G.L.)
| | - Serena Giannelli
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, 10043 Orbassano, Italy; (G.T.); (S.G.); (E.S.); (R.C.); (L.F.); (P.G.); (G.L.)
- Division of Neurology Vand Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy
| | - Erica Staurenghi
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, 10043 Orbassano, Italy; (G.T.); (S.G.); (E.S.); (R.C.); (L.F.); (P.G.); (G.L.)
| | - Rebecca Cecci
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, 10043 Orbassano, Italy; (G.T.); (S.G.); (E.S.); (R.C.); (L.F.); (P.G.); (G.L.)
| | - Lucrezia Floro
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, 10043 Orbassano, Italy; (G.T.); (S.G.); (E.S.); (R.C.); (L.F.); (P.G.); (G.L.)
| | - Paola Gamba
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, 10043 Orbassano, Italy; (G.T.); (S.G.); (E.S.); (R.C.); (L.F.); (P.G.); (G.L.)
| | - Barbara Sottero
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, 10043 Orbassano, Italy; (G.T.); (S.G.); (E.S.); (R.C.); (L.F.); (P.G.); (G.L.)
| | - Gabriella Leonarduzzi
- Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, 10043 Orbassano, Italy; (G.T.); (S.G.); (E.S.); (R.C.); (L.F.); (P.G.); (G.L.)
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Li Z, Zhu L, Xu Y, Zhang Y, Liu Y, Sun H, Li S, Wang M, Jiang T, Zhou J, Deng Q. Pleiotropic Effects of PCSK9 Inhibitors on Cardio-Cerebrovascular Diseases. Biomedicines 2024; 12:2729. [PMID: 39767636 PMCID: PMC11726846 DOI: 10.3390/biomedicines12122729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 11/21/2024] [Accepted: 11/26/2024] [Indexed: 01/16/2025] Open
Abstract
Cardiovascular disease (CVD) and ischemic stroke (IS) are the primary causes of mortality worldwide. Hypercholesterolemia has been recognized as an independent risk factor for CVD and IS. Numerous clinical trials have unequivocally demonstrated that reducing levels of low-density lipoprotein cholesterol (LDL-C) significantly mitigates the risk of both cardiac and cerebral vascular events, thereby enhancing patient prognosis. Consequently, LDL-C reduction remains a pivotal therapeutic strategy for CVD and IS. However, despite intensive statin therapy, a significant proportion of high-risk hypercholesterolemic patients fail to achieve sufficient reductions in LDL-C levels. In response to this challenge, an inhibitor targeting proprotein convertase subtilisin-kexin type 9 (PCSK9) has been developed as a therapeutic intervention for hyperlipidemia. Numerous randomized controlled trials (RCTs) have conclusively demonstrated that the combination of PCSK9 inhibitors and statins significantly enhances prognosis not only in patients with CVD, but also in those afflicted with symptomatic intracranial artery stenosis (sICAS). PCSK9 inhibitors significantly reduce LDL-C levels by binding to the PCSK9 molecule and preventing its interaction with LDLRs. This prevents degradation of the receptor and increases uptake of LDL-C, thereby decreasing its concentration in blood. Besides significantly reducing LDL-C levels, PCSK9 inhibitors also demonstrate anti-inflammatory and anti-atherosclerotic properties while promoting plaque stabilization and inhibiting platelet aggregation and thrombosis. This article aims to provide a comprehensive review based on the relevant literature regarding the evolving understanding of pleiotropic effects associated with PCSK9 inhibitors, particularly focusing on their impact on the cardiovascular system and central nervous system.
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Affiliation(s)
- Zhenzhen Li
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (Z.L.); (L.Z.); (Y.Z.); (Y.L.); (S.L.); (M.W.); (T.J.)
| | - Lin Zhu
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (Z.L.); (L.Z.); (Y.Z.); (Y.L.); (S.L.); (M.W.); (T.J.)
| | - Yeqiong Xu
- Central Laboratory of Changshu Medical Examination Institute, Changshu 215500, China;
| | - Yiting Zhang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (Z.L.); (L.Z.); (Y.Z.); (Y.L.); (S.L.); (M.W.); (T.J.)
| | - Yukai Liu
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (Z.L.); (L.Z.); (Y.Z.); (Y.L.); (S.L.); (M.W.); (T.J.)
| | - Huiling Sun
- General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China;
| | - Shuo Li
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (Z.L.); (L.Z.); (Y.Z.); (Y.L.); (S.L.); (M.W.); (T.J.)
| | - Meng Wang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (Z.L.); (L.Z.); (Y.Z.); (Y.L.); (S.L.); (M.W.); (T.J.)
| | - Teng Jiang
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (Z.L.); (L.Z.); (Y.Z.); (Y.L.); (S.L.); (M.W.); (T.J.)
| | - Junshan Zhou
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (Z.L.); (L.Z.); (Y.Z.); (Y.L.); (S.L.); (M.W.); (T.J.)
| | - Qiwen Deng
- Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China; (Z.L.); (L.Z.); (Y.Z.); (Y.L.); (S.L.); (M.W.); (T.J.)
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Papafaklis MI, Koros R, Tsigkas G, Karanasos A, Moulias A, Davlouros P. Reversal of Atherosclerotic Plaque Growth and Vulnerability: Effects of Lipid-Modifying and Anti-Inflammatory Therapeutic Agents. Biomedicines 2024; 12:2435. [PMID: 39595002 PMCID: PMC11591594 DOI: 10.3390/biomedicines12112435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/16/2024] [Accepted: 10/21/2024] [Indexed: 11/28/2024] Open
Abstract
Atherosclerotic plaque development constitutes the primary substrate of coronary artery disease (CAD) and is the outcome of an intricate process involving endothelial damage, inflammation, and lipid retention. The clinical efficacy of many lipid-lowering therapies in patients with CAD has been well established. Over the past few decades, a substantial and significant advance regarding the use of invasive and non-invasive imaging modalities has been observed. Numerous studies have been conducted using these imaging techniques and have investigated the changes in morphology (e.g., atheroma volume) and composition (e.g., lipid burden, fibrous cap thickness, macrophage accumulation) at the plaque level that explain the improved clinical outcomes by various pharmacological interventions. Lipid-lowering agents, such as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, demonstrate direct effects on plaque volume and composition that enhance plaque stabilization and/or regression beyond the reduction of low-density lipoproteins. An increasing amount of clinical research is also focused on the role of inflammation in plaque vulnerability and future adverse cardiac events. Consequently, there is a pressing need to explore therapeutic strategies that are capable of disrupting the inflammatory response as well as reducing atheroma burden and modifying high-risk plaque characteristics. This review provides a comprehensive analysis of the current evidence regarding the effects of traditional and novel therapeutic strategies targeting modification of the lipid profile and inflammatory processes on reversing plaque growth and attenuating vulnerable features, thereby promoting plaque stabilization and passivation.
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Affiliation(s)
- Michail I. Papafaklis
- Faculty of Medicine, University of Patras, 26504 Rio, Greece
- Cardiology Division, University Hospital of Patras, 26504 Rio, Greece
| | - Rafail Koros
- Cardiology Division, University Hospital of Patras, 26504 Rio, Greece
| | - Grigorios Tsigkas
- Faculty of Medicine, University of Patras, 26504 Rio, Greece
- Cardiology Division, University Hospital of Patras, 26504 Rio, Greece
| | - Antonios Karanasos
- Faculty of Medicine, University of Patras, 26504 Rio, Greece
- Cardiology Division, University Hospital of Patras, 26504 Rio, Greece
| | | | - Periklis Davlouros
- Faculty of Medicine, University of Patras, 26504 Rio, Greece
- Cardiology Division, University Hospital of Patras, 26504 Rio, Greece
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Giordano S, Ielapi J, Salerno N, Cersosimo A, Lucchino A, Laschera A, Canino G, Di Costanzo A, De Rosa S, Torella D, Sorrentino S. Rationale for Early Administration of PCSK9 Inhibitors in Acute Coronary Syndrome. Rev Cardiovasc Med 2024; 25:374. [PMID: 39484117 PMCID: PMC11522761 DOI: 10.31083/j.rcm2510374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 07/02/2024] [Accepted: 07/08/2024] [Indexed: 11/03/2024] Open
Abstract
Acute coronary syndromes (ACSs) represent a significant global health challenge arising from atherosclerotic cardiovascular disease (ASCVD), with elevated low-density lipoprotein cholesterol (LDL-C) levels being a primary contributor. Despite standard statin therapy, individuals with ACS remain at high risk for recurrent cardiovascular events, particularly in the initial post-ACS period. Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), such as evolocumab and alirocumab, offer a potential strategy to reduce LDL-C levels further and mitigate this residual risk. This review delves into the molecular mechanisms, effects on cholesterol metabolism, inflammatory modulation, and clinical outcomes associated with early administration of PCSK9 inhibitors following ACS.
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Affiliation(s)
- Salvatore Giordano
- Department of Medical and Surgical Sciences, Division of Cardiology, “Magna Graecia" University, 88100 Catanzaro, Italy
| | - Jessica Ielapi
- Department of Experimental and Clinical Medicine, “Magna Graecia" University, 88100 Catanzaro, Italy
| | - Nadia Salerno
- Department of Experimental and Clinical Medicine, “Magna Graecia" University, 88100 Catanzaro, Italy
| | - Angelica Cersosimo
- Department of Experimental and Clinical Medicine, “Magna Graecia" University, 88100 Catanzaro, Italy
| | - Alessandro Lucchino
- Department of Medical and Surgical Sciences, Division of Cardiology, “Magna Graecia" University, 88100 Catanzaro, Italy
| | - Alessandro Laschera
- Department of Medical and Surgical Sciences, Division of Cardiology, “Magna Graecia" University, 88100 Catanzaro, Italy
| | - Giovanni Canino
- Department of Medical and Surgical Sciences, Division of Cardiology, “Magna Graecia" University, 88100 Catanzaro, Italy
| | - Assunta Di Costanzo
- Department of Medical and Surgical Sciences, Division of Cardiology, “Magna Graecia" University, 88100 Catanzaro, Italy
| | - Salvatore De Rosa
- Department of Medical and Surgical Sciences, Division of Cardiology, “Magna Graecia" University, 88100 Catanzaro, Italy
| | - Daniele Torella
- Department of Experimental and Clinical Medicine, “Magna Graecia" University, 88100 Catanzaro, Italy
| | - Sabato Sorrentino
- Department of Medical and Surgical Sciences, Division of Cardiology, “Magna Graecia" University, 88100 Catanzaro, Italy
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Cao Zhang AM, Ziogos E, Harb T, Gerstenblith G, Leucker TM. Emerging clinical role of proprotein convertase subtilisin/kexin type 9 inhibition-Part one: Pleiotropic pro-atherosclerotic effects of PCSK9. Eur J Clin Invest 2024; 54:e14273. [PMID: 38922860 DOI: 10.1111/eci.14273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 05/20/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024]
Abstract
BACKGROUND Proprotein convertase subtilisin/kexin type 9 (PCSK9) is primarily recognized for its role in lipid metabolism, but recent evidence suggests that it may have broader implications due to its diverse tissue expression. OBJECTIVE This review aims to explore the multifaceted functions of PCSK9, highlighting its pro-atherosclerotic effects, including its impact on circulating lipoprotein variables, non-low-density lipoprotein receptors, and various cell types involved in atherosclerotic plaque development. CONCLUSIONS PCSK9 exhibits diverse roles beyond lipid metabolism, potentially contributing to atherosclerosis through multiple pathways. Understanding these mechanisms could offer new insights into therapeutic strategies targeting PCSK9 for cardiovascular disease management.
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Affiliation(s)
- Alexander M Cao Zhang
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Efthymios Ziogos
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Tarek Harb
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Gary Gerstenblith
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Thorsten M Leucker
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Dutka M, Zimmer K, Ćwiertnia M, Ilczak T, Bobiński R. The role of PCSK9 in heart failure and other cardiovascular diseases-mechanisms of action beyond its effect on LDL cholesterol. Heart Fail Rev 2024; 29:917-937. [PMID: 38886277 PMCID: PMC11306431 DOI: 10.1007/s10741-024-10409-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/11/2024] [Indexed: 06/20/2024]
Abstract
Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a protein that regulates low-density lipoprotein (LDL) cholesterol metabolism by binding to the hepatic LDL receptor (LDLR), ultimately leading to its lysosomal degradation and an increase in LDL cholesterol (LDLc) levels. Treatment strategies have been developed based on blocking PCSK9 with specific antibodies (alirocumab, evolocumab) and on blocking its production with small regulatory RNA (siRNA) (inclisiran). Clinical trials evaluating these drugs have confirmed their high efficacy in reducing serum LDLc levels and improving the prognosis in patients with atherosclerotic cardiovascular diseases. Most studies have focused on the action of PCSK9 on LDLRs and the subsequent increase in LDLc concentrations. Increasing evidence suggests that the adverse cardiovascular effects of PCSK9, particularly its atherosclerotic effects on the vascular wall, may also result from mechanisms independent of its effects on lipid metabolism. PCSK9 induces the expression of pro-inflammatory cytokines contributing to inflammation within the vascular wall and promotes apoptosis, pyroptosis, and ferroptosis of cardiomyocytes and is thus involved in the development and progression of heart failure. The elimination of PCSK9 may, therefore, not only be a treatment for hypercholesterolaemia but also for atherosclerosis and other cardiovascular diseases. The mechanisms of action of PCSK9 in the cardiovascular system are not yet fully understood. This article reviews the current understanding of the mechanisms of PCSK9 action in the cardiovascular system and its contribution to cardiovascular diseases. Knowledge of these mechanisms may contribute to the wider use of PCSK9 inhibitors in the treatment of cardiovascular diseases.
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Affiliation(s)
- Mieczysław Dutka
- Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa St. 2, 43-309, Bielsko-Biała, Poland.
| | - Karolina Zimmer
- Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa St. 2, 43-309, Bielsko-Biała, Poland
| | - Michał Ćwiertnia
- Department of Emergency Medicine, Faculty of Health Sciences, University of Bielsko-Biala, 43-309, Bielsko-Biała, Poland
| | - Tomasz Ilczak
- Department of Emergency Medicine, Faculty of Health Sciences, University of Bielsko-Biala, 43-309, Bielsko-Biała, Poland
| | - Rafał Bobiński
- Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, University of Bielsko-Biala, Willowa St. 2, 43-309, Bielsko-Biała, Poland
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9
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Ma Y, Fan H, Mi W, Ma J, Deng Y, Song Y, Li X. Proprotein convertase subtilisin/kexin type 9 inhibitors protect against contrast-associated acute kidney injury in patients with atherosclerotic cardiovascular disease. Front Cardiovasc Med 2024; 11:1384523. [PMID: 39055658 PMCID: PMC11269114 DOI: 10.3389/fcvm.2024.1384523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 06/25/2024] [Indexed: 07/27/2024] Open
Abstract
Background and aims Contrast-associated acute kidney injury (CA-AKI) may occur in patients undergoing medical procedures involving x-rays and radiocontrast media, potentially resulting in prolonged renal impairment. However, no effective treatments are available. Therefore, this study aimed to investigate the efficacy of evolocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in reducing CA-AKI incidence among patients with atherosclerotic cardiovascular disease (ASCVD) undergoing percutaneous coronary intervention. Methods This retrospective cohort study included patients who underwent percutaneous coronary intervention between January 2020 and December 2021 at Tianjin Chest Hospital. The study endpoint was CA-AKI incidence, and the impact of selection bias and other potential confounding factors was mitigated using bias matching. Overall, 1,642 patients were included in this study: 821 patients received evolocumab treatment before contrast agent application, and 821 did not receive such treatment. Results CA-AKI incidence was 6.21% and 8.04% in the evolocumab and control groups, respectively. After propensity-score matching, the incidence rate was 5.09% and 14.16% in the evolocumab and control groups, respectively. Evolocumab treatment significantly reduced CA-AKI incidence (p < 0.001). Consistent findings were obtained in the subgroups of individuals with type II diabetes mellitus, chronic heart failure, and hypertension. Evolocumab exhibited a significantly greater protective effect in the high- and extremely high-risk populations than in the low- and middle-risk populations (p < 0.001). Conclusions Evolocumab administration significantly reduced CA-AKI incidence among patients with ASCVD. Notably, this effect was more prominent within the subset of high- and extremely high-risk individuals who were already experiencing CA-AKI.
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Affiliation(s)
- Yu Ma
- Department of Cardiology, Chest Hospital, Tianjin University, Tianjin, China
- Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Tianjin, China
| | - Hui Fan
- Clinical School of Thoracic, Tianjin Medical University, Tianjin, China
| | - Wei Mi
- Department of Pharmacy, Chest Hospital, Tianjin University, Tianjin, China
| | - Jing Ma
- Tianjin Institute of Cardiovascular Diseases, Chest Hospital, Tianjin University, Tianjin, China
| | - Yong Deng
- Network Management Center, Chest Hospital, Tianjin University, Tianjin, China
| | - Yijie Song
- Network Management Center, Chest Hospital, Tianjin University, Tianjin, China
| | - Ximing Li
- Department of Cardiology, Chest Hospital, Tianjin University, Tianjin, China
- Tianjin Key Laboratory of Cardiovascular Emergency and Critical Care, Tianjin Municipal Science and Technology Bureau, Tianjin, China
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10
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Chong S, Mu G, Cen X, Xiang Q, Cui Y. Effects of PCSK9 on thrombosis and haemostasis in a variety of metabolic states: Lipids and beyond (Review). Int J Mol Med 2024; 53:57. [PMID: 38757360 PMCID: PMC11093556 DOI: 10.3892/ijmm.2024.5381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 04/22/2024] [Indexed: 05/18/2024] Open
Abstract
Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are widely recognised as being able to induce a potent reduction in low‑density lipoprotein‑cholesterol. An increasing number of studies have suggested that PCSK9 also influences the haemostatic system by altering platelet function and the coagulation cascade. These findings have significant implications for anti‑PCSK9 therapy in patients with specific coagulation conditions, including expanded indications, dose adjustments and drug interactions. The present review summarises the changes in PCSK9 levels in individuals with liver diseases, chronic kidney diseases, diabetes mellitus, cancer and other disease states, and discusses their impact on thrombosis and haemostasis. Furthermore, the structure, effects and regulatory mechanisms of PCSK9 on platelets, coagulation factors, inflammatory cells and endothelial cells during coagulation and haemostasis are described.
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Affiliation(s)
- Shan Chong
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100191, P.R. China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China
| | - Guangyan Mu
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100191, P.R. China
- Department of Pharmacy, Peking University First Hospital, Beijing 100034, P.R. China
| | - Xinan Cen
- Department of Hematology, Peking University First Hospital, Beijing 100034, P.R. China
| | - Qian Xiang
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100191, P.R. China
- Department of Pharmacy, Peking University First Hospital, Beijing 100034, P.R. China
| | - Yimin Cui
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing 100191, P.R. China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China
- Department of Pharmacy, Peking University First Hospital, Beijing 100034, P.R. China
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11
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Bagheri B, Khatibiyan Feyzabadi Z, Nouri A, Azadfallah A, Mahdizade Ari M, Hemmati M, Darban M, Alavi Toosi P, Banihashemian SZ. Atherosclerosis and Toll-Like Receptor4 (TLR4), Lectin-Like Oxidized Low-Density Lipoprotein-1 (LOX-1), and Proprotein Convertase Subtilisin/Kexin Type9 (PCSK9). Mediators Inflamm 2024; 2024:5830491. [PMID: 38445291 PMCID: PMC10914434 DOI: 10.1155/2024/5830491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 01/31/2024] [Accepted: 02/16/2024] [Indexed: 03/07/2024] Open
Abstract
Atherosclerosis is a leading cause of death in the world. A significant body of evidence suggests that inflammation and various players are implicated and have pivotal roles in the formation of atherosclerotic plaques. Toll-like receptor 4 (TLR4) is linked with different stages of atherosclerosis. This receptor is highly expressed in the endothelial cells (ECs) and atherosclerotic plaques. TLR4 activation can lead to the production of inflammatory cytokines and related responses. Lectin-like oxidized low-density lipoprotein-1 (LOX-1), an integral membrane glycoprotein with widespread expression on the ECs, is involved in atherosclerosis and has some common pathways with TLR4 in atherosclerotic lesions. In addition, proprotein convertase subtilisin/kexin type9 (PCSK9), which is a regulatory enzyme with different roles in cholesterol uptake, is implicated in atherosclerosis. At present, TLR4, PCSK9, and LOX-1 are increasingly acknowledged as key players in the pathogenesis of atherosclerotic cardiovascular diseases. Herein, we presented the current evidence on the structure, functions, and roles of TLR4, PCSK9, and LOX-1 in atherosclerosis.
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Affiliation(s)
- Bahador Bagheri
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Center for Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | | | - Ahmad Nouri
- Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Ali Azadfallah
- Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Mahyar Mahdizade Ari
- Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Maral Hemmati
- Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
| | - Mahboubeh Darban
- Department of Internal Medicine, Kowsar Hospital, Semnan University of Medical Sciences, Semnan, Iran
| | - Parisa Alavi Toosi
- Student Research Committee, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
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12
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Domingo E, Marques P, Francisco V, Piqueras L, Sanz MJ. Targeting systemic inflammation in metabolic disorders. A therapeutic candidate for the prevention of cardiovascular diseases? Pharmacol Res 2024; 200:107058. [PMID: 38218355 DOI: 10.1016/j.phrs.2024.107058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 12/11/2023] [Accepted: 01/03/2024] [Indexed: 01/15/2024]
Abstract
Cardiovascular disease (CVD) remains the leading cause of death and disability worldwide. While many factors can contribute to CVD, atherosclerosis is the cardinal underlying pathology, and its development is associated with several metabolic risk factors including dyslipidemia and obesity. Recent studies have definitively demonstrated a link between low-grade systemic inflammation and two relevant metabolic abnormalities: hypercholesterolemia and obesity. Interestingly, both metabolic disorders are also associated with endothelial dysfunction/activation, a proinflammatory and prothrombotic phenotype of the endothelium that involves leukocyte infiltration into the arterial wall, one of the earliest stages of atherogenesis. This article reviews the current literature on the intricate relationship between hypercholesterolemia and obesity and the associated systemic inflammation and endothelial dysfunction, and discusses the effectiveness of present, emerging and in-development pharmacological therapies used to treat these metabolic disorders with a focus on their effects on the associated systemic inflammatory state and cardiovascular risk.
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Affiliation(s)
- Elena Domingo
- Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain
| | - Patrice Marques
- Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain
| | - Vera Francisco
- Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; Endocrinology and Nutrition Service, University Clinic Hospital of Valencia, Valencia, Spain
| | - Laura Piqueras
- Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain; CIBERDEM, Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders, Carlos III Health Institute (ISCIII), Spain.
| | - Maria-Jesus Sanz
- Institute of Health Research INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain; Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain; CIBERDEM, Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders, Carlos III Health Institute (ISCIII), Spain.
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13
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Macvanin MT, Gluvic ZM, Klisic AN, Manojlovic MS, Suri JS, Rizzo M, Isenovic ER. The Link between miRNAs and PCKS9 in Atherosclerosis. Curr Med Chem 2024; 31:6926-6956. [PMID: 37990898 DOI: 10.2174/0109298673262124231102042914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/30/2023] [Accepted: 09/11/2023] [Indexed: 11/23/2023]
Abstract
Cardiovascular disease (CDV) represents the major cause of death globally. Atherosclerosis, as the primary cause of CVD, is a chronic immune-inflammatory disorder with complex multifactorial pathophysiology encompassing oxidative stress, enhanced immune-inflammatory cascade, endothelial dysfunction, and thrombosis. An initiating event in atherosclerosis is the subendothelial accumulation of low-density lipoprotein (LDL), followed by the localization of macrophages to fatty deposits on blood vessel walls, forming lipid-laden macrophages (foam cells) that secrete compounds involved in plaque formation. Given the fact that foam cells are one of the key culprits that underlie the pathophysiology of atherosclerosis, special attention has been paid to the investigation of the efficient therapeutic approach to overcome the dysregulation of metabolism of cholesterol in macrophages, decrease the foam cell formation and/or to force its degradation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory serine proteinase that has emerged as a significant regulator of the lipid metabolism pathway. PCSK9 activation leads to the degradation of LDL receptors (LDLRs), increasing LDL cholesterol (LDL-C) levels in the circulation. PCSK9 pathway dysregulation has been identified as one of the mechanisms involved in atherosclerosis. In addition, microRNAs (miRNAs) are investigated as important epigenetic factors in the pathophysiology of atherosclerosis and dysregulation of lipid metabolism. This review article summarizes the recent findings connecting the role of PCSK9 in atherosclerosis and the involvement of various miRNAs in regulating the expression of PCSK9-related genes. We also discuss PCSK9 pathway-targeting therapeutic interventions based on PCSK9 inhibition, and miRNA levels manipulation by therapeutic agents.
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Affiliation(s)
- Mirjana T Macvanin
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Zoran M Gluvic
- Department of Endocrinology and Diabetes, School of Medicine, University Clinical-Hospital Centre Zemun-Belgrade, Clinic of Internal Medicine, University of Belgrade, Belgrade, Serbia
| | - Aleksandra N Klisic
- Faculty of Medicine, Center for Laboratory Diagnostic, Primary Health Care Center, University of Montenegro, Podgorica, Montenegro
| | - Mia S Manojlovic
- Faculty of Medicine Novi Sad, University of Novi Sad, Novi Sad, Serbia
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Center of Vojvodina, Novi Sad, Serbia
| | - Jasjit S Suri
- Stroke Monitoring and Diagnostic Division, Athero- Point™, Roseville, CA95661, USA
| | - Manfredi Rizzo
- Department of Health Promotion, School of Medicine, Mother and Child Care and Medical Specialties (Promise), University of Palermo, Palermo, Italy
| | - Esma R Isenovic
- Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia
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14
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Zhao J, Wang R, Song L, Han H, Wang P, Zhao Y, Zhang Y, Zhang H. Causal association between lipid-lowering drugs and female reproductive endocrine diseases: a drug-targeted Mendelian randomization study. Front Endocrinol (Lausanne) 2023; 14:1295412. [PMID: 38027179 PMCID: PMC10668027 DOI: 10.3389/fendo.2023.1295412] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 10/30/2023] [Indexed: 12/01/2023] Open
Abstract
Purpose The relationship between dyslipidemia and female reproductive endocrine diseases has been increasingly studied. The use of lipid-lowering drugs in treating various related diseases, including coronary heart disease, may affect female reproductive endocrine diseases. Therefore, our study aims to investigate the effects of lipid-lowering drugs on female reproductive endocrine diseases and provide a basis for the appropriate selection of drugs. Methods In this study, we focused on three drug targets of statins, namely HMG-CoA reductase (HMGCR) inhibitors, proprotein convertase kexin 9 (PCSK9) inhibitors, and Niemann-Pick C1-Like 1 (NPC1L1) inhibitors. To identify potential inhibitors for these targets, we collected single nucleotide polymorphisms (SNPs) associated with HMGCR, PCSK9, and NPC1L1 from published genome-wide association study statistics. Subsequently, we conducted a drug target Mendelian randomization (MR) analysis to investigate the effects of these inhibitors on reproductive endocrine diseases mediated by low-density lipoprotein cholesterol (LDL-C) levels. Alongside coronary heart disease as a positive control, our main outcomes of interest included the risk of polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), premenstrual syndrome (PMS), abnormal uterine bleeding (including menorrhagia and oligomenorrhea), and infertility. Results PCSK9 inhibitors significantly increased the risk of infertility in patients (OR [95%CI] = 1.14 [1.06, 1.23], p<0.05). In contrast, HMGCR inhibitors significantly reduced the risk of menorrhagia in female patients (OR [95%CI] = 0.85 [0.75, 0.97], p<0.05), but had no statistical impact on patients with oligomenorrhea. Conclusion The findings suggest that PCSK9 inhibitors may significantly increase the risk of infertility in patients. On the other hand, HMGCR inhibitors could potentially offer protection against menorrhagia in women. However, no effects of lipid-lowering drugs have been observed on other reproductive endocrine disorders, such as PCOS, POF, PMS and oligomenorrhea.
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Affiliation(s)
- Jing Zhao
- Department of Gynecology, Hebei General Hospital, Shijiazhuang, China
| | - Runfang Wang
- Department of Obstetrics, Hebei General Hospital, Shijiazhuang, China
| | - Liyun Song
- Department of Gynecology, Hebei General Hospital, Shijiazhuang, China
| | - Hua Han
- Department of Gynecology, Hebei General Hospital, Shijiazhuang, China
| | - Pei Wang
- Department of Gynecology, Hebei General Hospital, Shijiazhuang, China
| | - Yuan Zhao
- Department of Clinical Laboratories, Kunhua Affiliated Hospital, Kunming University of Science and Technology, Kunming, China
| | - Yunxia Zhang
- Department of Gynecology, Hebei General Hospital, Shijiazhuang, China
| | - Hongzhen Zhang
- Department of Obstetrics and Gynecology, The First Hospital of Hebei Medical University, Shijiazhuang, China
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15
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Fang H, Lin D, Li X, Wang L, Yang T. Therapeutic potential of Ganoderma lucidum polysaccharide peptide in Doxorubicin-induced nephropathy: modulation of renin-angiotensin system and proteinuria. Front Pharmacol 2023; 14:1287908. [PMID: 37841924 PMCID: PMC10570435 DOI: 10.3389/fphar.2023.1287908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 09/21/2023] [Indexed: 10/17/2023] Open
Abstract
Introduction: In the Doxorubicin (DOX)-induced nephropathy model, proteinuria is a manifestation of progressive kidney injury. The pathophysiology of renal illness is heavily influenced by the renin-angiotensin system (RAS). To reduce renal RAS activation and proteinuria caused by DOX, this study evaluated the effectiveness of Ganoderma lucidum polysaccharide peptide (GL-PP), a new glycopeptide produced from Ganoderma lucidum grown on grass. Methods: Three groups of BALB/c male mice were created: control, DOX, and DOX + GL-PP. GL-PP (100 mg/kg) was administered to mice by intraperitoneal injection for 4 weeks following a single intravenous injection of DOX (10 mg/kg via the tail vein). Results: After 4 weeks, full-length and soluble pro(renin) receptor (fPRR/sPRR) overexpression in DOX mouse kidneys, which is crucial for the RAS pathway, was dramatically inhibited by GL-PP therapy. Additionally, GL-PP successfully reduced elevation of urinary renin activity and angiotensin II levels, supporting the idea that GL-PP inhibits RAS activation. Moreover, GL-PP showed a considerable downregulation of nicotinamide adenine nucleotide phosphate oxidase 4 (NOX4) expression and a decrease in hydrogen peroxide (H2O2) levels. GL-PP treatment effectively reduced glomerular and tubular injury induced by DOX, as evidenced by decreased proteinuria, podocyte damage, inflammation, oxidative stress, apoptosis, and fibrosis. Discussion: GL-PP inhibits intrarenal PRR/sPRR-RAS activation and upregulation of NOX4 and H2O2, suggesting potential therapeutic approaches against DOX-induced nephropathy.
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Affiliation(s)
- Hui Fang
- Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, Shandong, China
| | - Dongmei Lin
- National Engineering Research Center of JUNCAO Technology, Fujian Agriculture and Forestry University, Fuzhou, Fujian, China
| | - Xinxuan Li
- Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, Shandong, China
| | - Lianfu Wang
- National Engineering Research Center of JUNCAO Technology, Fujian Agriculture and Forestry University, Fuzhou, Fujian, China
| | - Teng Yang
- Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang, Shandong, China
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16
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Atreya MR, Cvijanovich NZ, Fitzgerald JC, Weiss SL, Bigham MT, Jain PN, Schwarz AJ, Lutfi R, Nowak J, Allen GL, Thomas NJ, Grunwell JR, Baines T, Quasney M, Haileselassie B, Alder MN, Lahni P, Ripberger S, Ekunwe A, Campbell KR, Walley KR, Standage SW. Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1. Crit Care 2023; 27:250. [PMID: 37365661 PMCID: PMC10291783 DOI: 10.1186/s13054-023-04535-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Accepted: 06/19/2023] [Indexed: 06/28/2023] Open
Abstract
BACKGROUND Sepsis is associated with significant mortality. Yet, there are no efficacious therapies beyond antibiotics. PCSK9 loss-of-function (LOF) and inhibition, through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance, holds promise as a potential therapeutic approach among adults. In contrast, we have previously demonstrated higher mortality in the juvenile host. Given the potential pleiotropic effects of PCSK9 on the endothelium, beyond canonical effects on serum lipoproteins, both of which may influence sepsis outcomes, we sought to test the influence of PCSK9 LOF genotype on endothelial dysfunction. METHODS Secondary analyses of a prospective observational cohort of pediatric septic shock. Genetic variants of PCSK9 and LDLR genes, serum PCSK9, and lipoprotein concentrations were determined previously. Endothelial dysfunction markers were measured in day 1 serum. We conducted multivariable linear regression to test the influence of PCSK9 LOF genotype on endothelial markers, adjusted for age, complicated course, and low- and high-density lipoproteins (LDL and HDL). Causal mediation analyses to test impact of select endothelial markers on the association between PCSK9 LOF genotype and mortality. Juvenile Pcsk9 null and wildtype mice were subject to cecal slurry sepsis and endothelial markers were quantified. RESULTS A total of 474 patients were included. PCSK9 LOF was associated with several markers of endothelial dysfunction, with strengthening of associations after exclusion of those homozygous for the rs688 LDLR variant that renders it insensitive to PCSK9. Serum PCSK9 was not correlated with endothelial dysfunction. PCSK9 LOF influenced concentrations of Angiopoietin-1 (Angpt-1) upon adjusting for potential confounders including lipoprotein concentrations, with false discovery adjusted p value of 0.042 and 0.013 for models that included LDL and HDL, respectively. Causal mediation analysis demonstrated that the effect of PCSK9 LOF on mortality was mediated by Angpt-1 (p = 0.0008). Murine data corroborated these results with lower Angpt-1 and higher soluble thrombomodulin among knockout mice with sepsis relative to the wildtype. CONCLUSIONS We present genetic and biomarker association data that suggest a potential direct role of the PCSK9-LDLR pathway on Angpt-1 in the developing host with septic shock and warrant external validation. Further, mechanistic studies on the role of PCSK9-LDLR pathway on vascular homeostasis may lead to the development of pediatric-specific sepsis therapies.
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Affiliation(s)
- Mihir R Atreya
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, MLC200545229, USA.
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
| | | | | | - Scott L Weiss
- Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | | | - Parag N Jain
- Texas Children's Hospital and Baylor College of Medicine, Houston, TX, 77030, USA
| | - Adam J Schwarz
- Children's Hospital of Orange County, Orange, CA, 92868, USA
| | - Riad Lutfi
- Riley Hospital for Children, Indianapolis, IN, 46202, USA
| | - Jeffrey Nowak
- Children's Hospital and Clinics of Minnesota, Minneapolis, MN, 55404, USA
| | | | - Neal J Thomas
- Penn State Hershey Children's Hospital, Hershey, PA, 17033, USA
| | | | - Torrey Baines
- University of Florida Health Shands Children's Hospital, Gainesville, FL, 32610, USA
| | - Michael Quasney
- CS Mott Children's Hospital at the University of Michigan, Ann Arbor, MI, 48109, USA
| | | | - Matthew N Alder
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, MLC200545229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Patrick Lahni
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, MLC200545229, USA
| | - Scarlett Ripberger
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, MLC200545229, USA
| | - Adesuwa Ekunwe
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, MLC200545229, USA
| | - Kyle R Campbell
- Department of Medicine, Center for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada
| | - Keith R Walley
- Department of Medicine, Center for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, BC, V5Z 1M9, Canada
| | - Stephen W Standage
- Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, MLC200545229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
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Oza PP, Kashfi K. The evolving landscape of PCSK9 inhibition in cancer. Eur J Pharmacol 2023; 949:175721. [PMID: 37059376 PMCID: PMC10229316 DOI: 10.1016/j.ejphar.2023.175721] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/23/2023] [Accepted: 04/11/2023] [Indexed: 04/16/2023]
Abstract
Cancer is a disease with a significant global burden in terms of premature mortality, loss of productivity, healthcare expenditures, and impact on mental health. Recent decades have seen numerous advances in cancer research and treatment options. Recently, a new role of cholesterol-lowering PCSK9 inhibitor therapy has come to light in the context of cancer. PCSK9 is an enzyme that induces the degradation of low-density lipoprotein receptors (LDLRs), which are responsible for clearing cholesterol from the serum. Thus, PCSK9 inhibition is currently used to treat hypercholesterolemia, as it can upregulate LDLRs and enable cholesterol reduction through these receptors. The cholesterol-lowering effects of PCSK9 inhibitors have been suggested as a potential mechanism to combat cancer, as cancer cells have been found to increasingly rely on cholesterol for their growth needs. Additionally, PCSK9 inhibition has demonstrated the potential to induce cancer cell apoptosis through several pathways, increase the efficacy of a class of existing anticancer therapies, and boost the host immune response to cancer. A role in managing cancer- or cancer treatment-related development of dyslipidemia and life-threatening sepsis has also been suggested. This review examines the current evidence regarding the effects of PCSK9 inhibition in the context of different cancers and cancer-associated complications.
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Affiliation(s)
- Palak P Oza
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, 10031, USA
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY, 10031, USA; Graduate Program in Biology, City University of New York Graduate Center, New York, 10091, USA.
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18
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De Luca L, Riccio C, Navazio A, Valente S, Cipriani M, Corda M, De Nardo A, Francese GM, Napoletano C, Tizzani E, Roncon L, Caldarola P, Gulizia MM, Gabrielli D, Oliva F, Colivicchi F. ANMCO position paper on the management of hypercholesterolaemia in patients with acute coronary syndrome. Eur Heart J Suppl 2023; 25:D312-D322. [PMID: 37213800 PMCID: PMC10194822 DOI: 10.1093/eurheartjsupp/suad100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Patients suffering from acute coronary syndrome (ACS) present a high risk of recurrence and new adverse cardiovascular events after hospital discharge. Elevated plasma LDL-cholesterol (LDL-C) levels have been shown to be a causal factor for the development of coronary heart disease, and robust clinical evidence has documented that LDL-C levels decrease linearly correlates with a reduction in cardiovascular events. Recent studies have also demonstrated the safety and efficacy of an early and significant reduction in LDL-C levels in patients with ACS. In this position paper, Italian Association of Hospital Cardiologists proposes a decision algorithm on early adoption of lipid-lowering strategies at hospital discharge and short-term follow-up of patients with ACS, in the light of the multiple evidence generated in recent years on the treatment of hypercholesterolaemia and the available therapeutic options, considering current reimbursement criteria.
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Affiliation(s)
- Leonardo De Luca
- Corresponding author. Tel: 00390658704419, Fax: 00390658704423, ;
| | - Carmine Riccio
- UOSD Follow-up del Paziente Post-Acuto, Dipartimento Cardio-Vascolare, AORN Sant'Anna e San Sebastiano, Caserta 81100, Italy
| | - Alessandro Navazio
- SOC Cardiologia Ospedaliera, Presidio Ospedaliero Arcispedale Santa Maria Nuova, Azienda USL di Reggio Emilia—IRCCS, Reggio Emilia 42121, Italy
| | - Serafina Valente
- Dipartimento Cardio-Toracico, AOU Senese, Ospedale Santa Maria alle Scotte, Siena 53100, Italy
| | - Manlio Cipriani
- UOC Cardiologia, ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad alta specializzazione), Palermo 90121, Italy
| | - Marco Corda
- S.C. Cardiologia, Azienda Ospedaliera G. Brotzu, Cagliari 09121, Italy
| | - Alfredo De Nardo
- UO Cardiologia-UTIC, Ospedale Civile ‘G. Jazzolino’, Vibo Valentia 89900, Italy
| | - Giuseppina Maura Francese
- UOC Cardiologia, Ospedale Garibaldi-Nesima, Azienda di Rilievo Nazionale e Alta Specializzazione ‘Garibaldi’, Catania 95100, Italy
| | - Cosimo Napoletano
- UOC Cardiologia-UTIC-Emodinamica, Presidio Ospedaliero ‘G. Mazzini’, Teramo 64100, Italy
| | - Emanuele Tizzani
- Dipartimento di Cardiologia, Ospedale degli Infermi, Rivoli (TO), Torino 10098, Italy
| | - Loris Roncon
- UOC Cardiologia, Ospedale Santa Maria della Misericordia, Rovigo 45100, Italy
| | | | - Michele Massimo Gulizia
- UOC Cardiologia, Ospedale Garibaldi-Nesima, Azienda di Rilievo Nazionale e Alta Specializzazione ‘Garibaldi’, Catania 95100, Italy
| | - Domenico Gabrielli
- Dipartimento di Scienze Cardio-Toraco-Vascolari, UOC Cardiologia, AO San Camillo-Forlanini, Circonvallazione Gianicolense, 87, 00152 Roma, Italy
| | - Fabrizio Oliva
- Unità di Cure Intensive Cardiologiche, Cardiologia 1-Emodinamica, Dipartimento Cardiotoracovascolare ‘A. De Gasperis’, ASST Grande Ospedale Metropolitano Niguarda, Milano 20162, Italy
| | - Furio Colivicchi
- UOC Cardiologia Clinica e Riabilitativa, Presidio Ospedaliero San Filippo Neri—ASL Roma 1, Roma 00176, Italia
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Qian Y, Shi C, Cheng C, Liao D, Liu J, Chen GT. Ginger polysaccharide UGP1 suppressed human colon cancer growth via p53, Bax/Bcl-2, caspase-3 pathways and immunomodulation. FOOD SCIENCE AND HUMAN WELLNESS 2023. [DOI: 10.1016/j.fshw.2022.07.048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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20
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Atreya MR, Cvijanovich NZ, Fitzgerald JC, Weiss SL, Bigham MT, Jain PN, Schwarz AJ, Lutfi R, Nowak J, Allen GL, Thomas NJ, Grunwell JR, Baines T, Quasney M, Haileselassie B, Alder MN, Lahni P, Ripberger S, Ekunwe A, Campbell KR, Walley KR, Standage SW. Detrimental effects of PCSK9 loss-of-function in the pediatric host response to sepsis are mediated through independent influence on Angiopoietin-1. RESEARCH SQUARE 2023:rs.3.rs-2521836. [PMID: 36778250 PMCID: PMC9915797 DOI: 10.21203/rs.3.rs-2521836/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Background: Sepsis is associated with significant mortality, yet there are no efficacious therapies beyond antibiotics and supportive care. In adult sepsis studies, PCSK9 loss-of-function (LOF) and inhibition has shown therapeutic promise, likely through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance. In contrast, we previously demonstrated higher mortality in septic juvenile hosts with PCSK9 LOF. In addition to direct influence on serum lipoprotein levels, PCSK9 likely exerts pleiotropic effects on vascular endothelium. Both mechanisms may influence sepsis outcomes. We sought to test the influence of PCSK9 LOF genotype on endothelial dysfunction in pediatric sepsis. Methods: Secondary analyses of a prospective observational cohort of pediatric septic shock. Single nucleotide polymorphisms of PCSK9 and LDLR genes were assessed. Serum PCSK9, lipoprotein, and endothelial marker concentrations were measured. Multivariable linear regression tested the influence of PCSK9 LOF genotype on endothelial markers, adjusted for age, complicated course, and low- and high-density lipoproteins (LDL and HDL). Causal mediation analyses assessed impact of select endothelial markers on the association between PCSK9 LOF genotype and mortality. Juvenile Pcsk9 null and wildtype mice were subject to cecal slurry sepsis and endothelial markers were quantified. Results: 474 patients were included. PCSK9 LOF was associated with several markers of endothelial dysfunction, with strengthening of associations after exclusion of patients homozygous for the rs688 LDLR variant that renders it insensitive to PCSK9. Serum PCSK9 levels did not correlate with endothelial dysfunction. PCSK9 LOF significantly influenced concentrations of Angiopoietin-1 (Angpt-1) and Vascular Cell Adhesion Molecule-1 (VCAM-1). However, upon adjusting for LDL and HDL, PCSK9 LOF remained significantly associated with low Angpt-1 alone. Causal Mediation Analysis demonstrated that the effect of PCSK9 LOF on mortality was partially mediated by Angpt-1 (p=0.0008). Murine data corroborated these results with lower Angpt-1 and higher soluble thrombomodulin among knockout mice with sepsis relative to the wildtype. Conclusions: PCSK9 LOF independently influences serum Angpt-1 levels in pediatric septic shock. Angpt-1 likely contributes mechanistically to the effect of PCSK9 LOF on mortality in juvenile hosts. Mechanistic studies on the role of PCSK9-LDLR pathway on vascular homeostasis may lead to the development of novel pediatric-specific sepsis therapies.
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Affiliation(s)
| | | | | | | | | | - Parag N. Jain
- Texas Children’s Hospital, Baylor College of Medicine
| | | | | | | | | | | | | | - Torrey Baines
- University of Florida Health Shands Children’s Hospital
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21
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Xu Q, Zhao YM, He NQ, Gao R, Xu WX, Zhuo XJ, Ren Z, Wu CY, Liu LS. PCSK9: A emerging participant in heart failure. Biomed Pharmacother 2023; 158:114106. [PMID: 36535197 DOI: 10.1016/j.biopha.2022.114106] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/01/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022] Open
Abstract
Heart failure (HF) is a complex clinical syndrome caused by various cardiovascular diseases. Its main pathogenesis includes cardiomyocyte loss, myocardial energy metabolism disorder, and activation of cardiac inflammation. Due to the clinically unsatisfactory treatment of heart failure, different mechanisms need to be explored to provide new targets for the treatment of this disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a gene mainly related to familial hypercholesterolemia, was discovered in 2003. Aside from regulating lipid metabolism, PCSK9 may be involved in other biological processes such as apoptosis, autophagy, pyroptosis, inflammation, and tumor immunity and related to diabetes and neurodegenerative diseases. Recently, clinical data have shown that the circulating PCSK9 level is significantly increased in patients with heart failure, and it is related to the prognosis for heart failure. Furthermore, in animal models and patients with myocardial infarction, PCSK9 in the infarct margin area was also found to be significantly increased, which further suggested that PCSK9 might be closely related to heart failure. However, the specific mechanism of how PCSK9 participates in heart failure remains to be further explored. The purpose of this review is to summarize the potential mechanism of PCSK9's involvement in heart failure, thereby providing a new treatment strategy for heart failure.
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Affiliation(s)
- Qian Xu
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan Province 421001, PR China
| | - Yi-Meng Zhao
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan Province 421001, PR China
| | - Nai-Qi He
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan Province 421001, PR China
| | - Rong Gao
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan Province 421001, PR China
| | - Wen-Xin Xu
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan Province 421001, PR China
| | - Xiu-Juan Zhuo
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan Province 421001, PR China
| | - Zhong Ren
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan Province 421001, PR China
| | - Chun-Yan Wu
- The Third Affiliated Hospital, Department of Cardiovascular Medicine, University of South China, Hengyang, Hunan Province 421001, PR China.
| | - Lu-Shan Liu
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan Province 421001, PR China.
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22
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Sotler T, Šebeštjen M. PCSK9 as an Atherothrombotic Risk Factor. Int J Mol Sci 2023; 24:ijms24031966. [PMID: 36768292 PMCID: PMC9916735 DOI: 10.3390/ijms24031966] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/15/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Disturbances in lipid metabolism are among the most important risk factors for atherosclerotic cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key protein in lipid metabolism that is also involved in the production of inflammatory cytokines, endothelial dysfunction and aherosclerotic plaque development. Studies have shown a connection between PCSK9 and various indicators of inflammation. Signalling pathways that include PCSK9 play important role in the initiation and development of atherosclerotic lesions by inducing vascular inflammation. Studies so far have suggested that PCSK9 is associated with procoagulation, enhancing the development of atherosclerosis. Experimentally, it was also found that an increased concentration of PCSK9 significantly accelerated the apoptosis of endothelial cells and reduced endothelial function, which created conditions for the development of atherosclerosis. PCSK9 inhibitors can therefore improve clinical outcomes not only in a lipid-dependent manner, but also through lipid-independent pathways. The aim of our review was to shed light on the impact of PCSK9 on these factors, which are not directly related to low-density lipoprotein (LDL) cholesterol metabolism.
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Affiliation(s)
- Tadeja Sotler
- Department of Cardiology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
| | - Miran Šebeštjen
- Department of Cardiology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
- Department of Vascular Diseases, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
- Correspondence:
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23
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Alannan M, Seidah NG, Merched AJ. PCSK9 in Liver Cancers at the Crossroads between Lipid Metabolism and Immunity. Cells 2022; 11:cells11244132. [PMID: 36552895 PMCID: PMC9777286 DOI: 10.3390/cells11244132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 12/01/2022] [Accepted: 12/06/2022] [Indexed: 12/23/2022] Open
Abstract
Metabolic rewiring and defective immune responses are considered to be the main driving forces sustaining cell growth and oncogenesis in many cancers. The atypical enzyme, proprotein convertase subtilisin/kexin type 9 (PCSK9), is produced by the liver in large amounts and plays a major role in lipid metabolism via the control of the low density lipoprotein receptor (LDLR) and other cell surface receptors. In this context, many clinical studies have clearly demonstrated the high efficacy of PCSK9 inhibitors in treating hyperlipidemia and cardiovascular diseases. Recent data implicated PCSK9 in the degradation of major histocompatibility complex I (MHC-I) receptors and the immune system as well as in other physiological activities. This review highlights the complex crosstalk between PCSK9, lipid metabolism and immunosuppression and underlines the latest advances in understanding the involvement of this convertase in other critical functions. We present a comprehensive assessment of the different strategies targeting PCSK9 and show how these approaches could be extended to future therapeutic options to treat cancers with a main focus on the liver.
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Affiliation(s)
- Malak Alannan
- Bordeaux Institute of Oncology (BRIC), INSERM U1312, University of Bordeaux, F-33000 Bordeaux, France
| | - Nabil G. Seidah
- Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute, IRCM, University of Montreal, Montreal, QC H2W 1R7, Canada
| | - Aksam J. Merched
- Bordeaux Institute of Oncology (BRIC), INSERM U1312, University of Bordeaux, F-33000 Bordeaux, France
- Correspondence:
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24
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Mensink FB, Los J, Ten Cate TJF, Oemrawsingh RM, Brouwer MA, El Messaoudi S, van Royen N, Cornel JH, Riksen NP, van Geuns RJM. Pharmaco-invasive therapy: Early implementation of statins and proprotein convertase subtilisin/kexin type 9 inhibitors after acute coronary syndrome. Front Cardiovasc Med 2022; 9:1061346. [PMID: 36568547 PMCID: PMC9772027 DOI: 10.3389/fcvm.2022.1061346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 11/14/2022] [Indexed: 12/12/2022] Open
Abstract
Elevated LDL-cholesterol (LDL-C) plays a major role in atheroma formation and inflammation. Medical therapy to lower elevated LDL-C is the cornerstone for reducing the progression of atherosclerotic cardiovascular disease. Statin therapy, and more recently, other drugs such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, have proven efficacy in long-term lowering of LDL-C and therefore diminish cardiovascular risk. During an acute coronary syndrome (ACS), a systemic inflammatory response can destabilize other non-culprit atherosclerotic plaques. Patients with these vulnerable plaques are at high risk of experiencing recurrent cardiovascular events in the first few years post-ACS. Initiating intensive LDL-C lowering therapy in these patients with statins or PCSK9 inhibitors can be beneficial via several pathways. High-intensity statin therapy can reduce inflammation by directly lowering LDL-C, but also through its pleiotropic effects. PCSK9 inhibitors can directly lower LDL-C to recommended guideline thresholds, and could have additional effects on inflammation and plaque stability. We discuss the potential role of early implementation of statins combined with PCSK9 inhibitors to influence these cascades and to mediate the associated cardiovascular risk, over and above the well-known long-term beneficial effects of chronic LDL-C lowering.
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Affiliation(s)
- F. B. Mensink
- Department of Cardiology, Radboud University Medical Center, Nijmegen, Netherlands,*Correspondence: F. B. Mensink,
| | - J. Los
- Department of Cardiology, Radboud University Medical Center, Nijmegen, Netherlands
| | - T. J. F. Ten Cate
- Department of Cardiology, Radboud University Medical Center, Nijmegen, Netherlands
| | - R. M. Oemrawsingh
- Department of Cardiology, Albert Schweitzer Ziekenhuis, Dordrecht, Netherlands
| | - M. A. Brouwer
- Department of Cardiology, Radboud University Medical Center, Nijmegen, Netherlands
| | - S. El Messaoudi
- Department of Cardiology, Radboud University Medical Center, Nijmegen, Netherlands
| | - N. van Royen
- Department of Cardiology, Radboud University Medical Center, Nijmegen, Netherlands
| | - J. H. Cornel
- Department of Cardiology, Noordwest Ziekenhuisgroep, Alkmaar, Netherlands
| | - N. P. Riksen
- Department of Cardiology, Radboud University Medical Center, Nijmegen, Netherlands
| | - R. J. M. van Geuns
- Department of Cardiology, Radboud University Medical Center, Nijmegen, Netherlands
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25
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Safaeian L, Mirian M, Bahrizadeh S. Evolocumab, a PCSK9 inhibitor, protects human endothelial cells against H 2O 2-induced oxidative stress. Arch Physiol Biochem 2022; 128:1681-1686. [PMID: 32619370 DOI: 10.1080/13813455.2020.1788605] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
CONTEXT Recent surveys have shown an association between proprotein convertase subtilisin/kexin type 9 (PCSK9) and oxidative stress. OBJECTIVE In this investigation, the effect of evolocumab an anti-PCSK9 antibody was assessed against oxidative damage caused by hydrogen peroxide (H2O2) in human umbilical vein endothelial cells (HUVEC). MATERIAL AND METHODS Viability of HUVEC was measured by MTT assay. Hydroperoxides and malondialdehyde (MDA) levels, and ferric reducing antioxidant power (FRAP) were detected in HUVEC that pre-treated with evolocumab and, then exposed to H2O2. RESULTS Evolocumab significantly prevented the cytotoxicity induced by H2O2 at the concentrations of 5-100 µg/ml. Pre-treatment of HUVEC with evolocumab reduced hydroperoxides and MDA levels and also increased FRAP value in intra- and extra-cellular mediums compared with H2O2 stimulated cells at different concentration ranges. CONCLUSION This study displayed anti-oxidative and cytoprotective activities of evolocumab against oxidative damage caused by H2O2 in endothelial cells.
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Affiliation(s)
- Leila Safaeian
- Department of Pharmacology and Toxicology, Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mina Mirian
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Shahryar Bahrizadeh
- Department of Pharmacology and Toxicology, Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
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26
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Wang X, Sun Z, Yuan R, Zhang W, Shen Y, Yin A, Li Y, Ji Q, Wang X, Li Y, Zhang M, Pan X, Shen L, He B. K-80003 Inhibition of Macrophage Apoptosis and Necrotic Core Development in Atherosclerotic Vulnerable Plaques. Cardiovasc Drugs Ther 2022; 36:1061-1073. [PMID: 34410548 PMCID: PMC9652240 DOI: 10.1007/s10557-021-07237-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/06/2021] [Indexed: 12/19/2022]
Abstract
PURPOSE Macrophage apoptosis coupled with a defective phagocytic clearance of the apoptotic cells promotes plaque necrosis in advanced atherosclerosis, which causes acute atherothrombotic vascular disease. Nonsteroidal anti-inflammatory drug sulindac derivative K-80003 treatment was previously reported to dramatically attenuate atherosclerotic plaque progression and destabilization. However, the underlying mechanisms are not fully understood. This study aimed to determine the role of K-80003 on macrophage apoptosis and elucidate the underlying mechanism. METHODS The mouse model of vulnerable carotid plaque in ApoE-/- mice was developed in vivo. Consequently, mice were randomly grouped into two study groups: the control group and the K-80003 group (30 mg/kg/day). Samples of carotid arteries were collected to determine atherosclerotic necrotic core area, cellular apoptosis, and oxidative stress. The effects of K-80003 on RAW264.7 macrophage apoptosis, oxidative stress, and autophagic flux were also examined in vitro. RESULTS K-80003 significantly suppressed necrotic core formation and inhibited cellular apoptosis of vulnerable plaques. K-80003 can also inhibit 7-ketocholesterol-induced macrophage apoptosis in vitro. Furthermore, K-80003 inhibited intraplaque cellular apoptosis mainly through the suppression of oxidative stress, which is a key cause of advanced lesional macrophage apoptosis. Mechanistically, K-80003 prevented 7-ketocholesterol-induced impairment of autophagic flux in macrophages, evidenced by the decreased LC3II and SQSTM1/p62 expression, GFP-RFP-LC3 cancellation upon K-80003 treatment. CONCLUSION Inhibition of macrophage apoptosis and necrotic core formation by autophagy-mediated reduction of oxidative stress is one mechanism of the suppression of plaque progression and destabilization by K-80003.
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Affiliation(s)
- Xiaolei Wang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui Distinct, 241 West Huaihai Road, Shanghai, China
| | - Zhe Sun
- School of Life Science and Technology, Shanghai Tech University, Shanghai, China
| | - Ruosen Yuan
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui Distinct, 241 West Huaihai Road, Shanghai, China
| | - Weifeng Zhang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui Distinct, 241 West Huaihai Road, Shanghai, China
| | - Yejiao Shen
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui Distinct, 241 West Huaihai Road, Shanghai, China
| | - Anwen Yin
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui Distinct, 241 West Huaihai Road, Shanghai, China
| | - Yanjie Li
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui Distinct, 241 West Huaihai Road, Shanghai, China
| | - Qingqi Ji
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui Distinct, 241 West Huaihai Road, Shanghai, China
| | - Xia Wang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui Distinct, 241 West Huaihai Road, Shanghai, China
| | - Yi Li
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui Distinct, 241 West Huaihai Road, Shanghai, China
| | - Min Zhang
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui Distinct, 241 West Huaihai Road, Shanghai, China
| | - Xin Pan
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui Distinct, 241 West Huaihai Road, Shanghai, China.
| | - Linghong Shen
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui Distinct, 241 West Huaihai Road, Shanghai, China.
| | - Ben He
- Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Xuhui Distinct, 241 West Huaihai Road, Shanghai, China
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27
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Katsuki S, K. Jha P, Lupieri A, Nakano T, Passos LS, Rogers MA, Becker-Greene D, Le TD, Decano JL, Ho Lee L, Guimaraes GC, Abdelhamid I, Halu A, Muscoloni A, V. Cannistraci C, Higashi H, Zhang H, Vromman A, Libby P, Keith Ozaki C, Sharma A, Singh SA, Aikawa E, Aikawa M. Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Promotes Macrophage Activation via LDL Receptor-Independent Mechanisms. Circ Res 2022; 131:873-889. [PMID: 36263780 PMCID: PMC9973449 DOI: 10.1161/circresaha.121.320056] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND Activated macrophages contribute to the pathogenesis of vascular disease. Vein graft failure is a major clinical problem with limited therapeutic options. PCSK9 (proprotein convertase subtilisin/kexin 9) increases low-density lipoprotein (LDL)-cholesterol levels via LDL receptor (LDLR) degradation. The role of PCSK9 in macrophage activation and vein graft failure is largely unknown, especially through LDLR-independent mechanisms. This study aimed to explore a novel mechanism of macrophage activation and vein graft disease induced by circulating PCSK9 in an LDLR-independent fashion. METHODS We used Ldlr-/- mice to examine the LDLR-independent roles of circulating PCSK9 in experimental vein grafts. Adeno-associated virus (AAV) vector encoding a gain-of-function mutant of PCSK9 (rAAV8/D377Y-mPCSK9) induced hepatic PCSK9 overproduction. To explore novel inflammatory targets of PCSK9, we used systems biology in Ldlr-/- mouse macrophages. RESULTS In Ldlr-/- mice, AAV-PCSK9 increased circulating PCSK9, but did not change serum cholesterol and triglyceride levels. AAV-PCSK9 promoted vein graft lesion development when compared with control AAV. In vivo molecular imaging revealed that AAV-PCSK9 increased macrophage accumulation and matrix metalloproteinase activity associated with decreased fibrillar collagen, a molecular determinant of atherosclerotic plaque stability. AAV-PCSK9 induced mRNA expression of the pro-inflammatory mediators IL-1β (interleukin-1 beta), TNFα (tumor necrosis factor alpha), and MCP-1 (monocyte chemoattractant protein-1) in peritoneal macrophages underpinned by an in vitro analysis of Ldlr-/- mouse macrophages stimulated with endotoxin-free recombinant PCSK9. A combination of unbiased global transcriptomics and new network-based hyperedge entanglement prediction analysis identified the NF-κB (nuclear factor-kappa B) signaling molecules, lectin-like oxidized LOX-1 (LDL receptor-1), and SDC4 (syndecan-4) as potential PCSK9 targets mediating pro-inflammatory responses in macrophages. CONCLUSIONS Circulating PCSK9 induces macrophage activation and vein graft lesion development via LDLR-independent mechanisms. PCSK9 may be a potential target for pharmacologic treatment for this unmet medical need.
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Affiliation(s)
- Shunsuke Katsuki
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Prabhash K. Jha
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Adrien Lupieri
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Toshiaki Nakano
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Livia S.A. Passos
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Maximillian A. Rogers
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
| | - Dakota Becker-Greene
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Thanh-Dat Le
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Julius L. Decano
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
| | - Lang Ho Lee
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
| | - Gabriel C. Guimaraes
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Ilyes Abdelhamid
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
- Channing Division of Network Medicine (I.A., A.H., A.S., M.A.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Arda Halu
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
- Channing Division of Network Medicine (I.A., A.H., A.S., M.A.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Alessandro Muscoloni
- The Biomedical Cybernetics Group, Biotechnology Center, Center for Molecular and Cellular Bioengineering, Center for Systems Biology Dresden, Cluster of Excellence Physics of Life, Department of Physics, Technical University Dresden, Dresden, Germany (A.M., C.V.C)
- Center for Complex Network Intelligence at the Tsinghua Laboratory of Brain and Intelligence, Department of Bioengineering, Tsinghua University, Beijing, China (A.M., C.V.C.)
| | - Carlo V. Cannistraci
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
- Center for Complex Network Intelligence at the Tsinghua Laboratory of Brain and Intelligence, Department of Bioengineering, Tsinghua University, Beijing, China (A.M., C.V.C.)
| | - Hideyuki Higashi
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
| | - Hengmin Zhang
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
| | - Amélie Vromman
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - Peter Libby
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
| | - C. Keith Ozaki
- Center for Complex Network Intelligence at the Tsinghua Laboratory of Brain and Intelligence, Department of Bioengineering, Tsinghua University, Beijing, China (A.M., C.V.C.)
| | - Amitabh Sharma
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
- Channing Division of Network Medicine (I.A., A.H., A.S., M.A.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Sasha A. Singh
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
| | - Elena Aikawa
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
| | - Masanori Aikawa
- The Center for Excellence in Vascular Biology, Cardiovascular Division (S.K., P.K.J., A.L., T.N., L.S.A.P., D.B.-G., T.-D.L., G.C.G., A.V., P.L., E.A., M.A.)
- The Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division (M.A.R., J.L.D., L.H.L., I.A., A.H., H.H., H.Z., A.S., S.A.S., E.A., M.A.)
- Channing Division of Network Medicine (I.A., A.H., A.S., M.A.), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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Sawaguchi J, Saeki Y, Oda M, Takamura TA, Fujibayashi K, Wakasa M, Akao H, Kitayama M, Kawai Y, Kajinami K. The circulating furin-cleaved/mature PCSK9 ratio has a potential prognostic significance in statin-naïve patients with acute ST elevation myocardial infarction. ATHEROSCLEROSIS PLUS 2022; 50:50-56. [PMID: 36643795 PMCID: PMC9833232 DOI: 10.1016/j.athplu.2022.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 09/09/2022] [Accepted: 09/26/2022] [Indexed: 01/18/2023]
Abstract
Background and aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) circulates as mature and furin-cleaved forms, but their biological functions are uncertain. We investigated whether their levels associate with prognosis in patients with acute ST elevation myocardial infarction (STEMI). Methods We enrolled 160 statin-naïve patients with acute STEMI and followed for 3 years. PCSK9 subtype levels were determined by an enzyme-linked immunosorbent assay before and at five timepoints up to 48 h after emergent coronary intervention. The occurrence of coronary and cardiac events was compared between subjects stratified by the PCSK9 level. Results One hundred and twenty-six patients completed 3 years of follow-up. In the acute phase, both PCSK9 subtype levels decreased, and thereafter increased from 6 to 48 h (mature: from 198 ± 67 to 334 ± 116 ng/mL, furin-cleaved: from 20 ± 7 to 39 ± 16 ng/mL, both p < 0.01). Major cardiac events occurred in 46 patients. The furin-cleaved/mature PCSK9 ratio at 48 h after coronary intervention predicted the likelihood of experiencing of events; patients in the third tertile had lower event-free survival than those in the first and second tetiles in Kaplan-Meier analysis (p = 0.004). Multivariate Cox regression analysis revealed that this ratio had a greater impact (HR: 1.92; 95% CI: 1.06-3.45, p = 0.03) on events than other known atherosclerosis risk factors. Conclusions The furin-cleaved/mature PCSK9 ratio was associated with 3-year cardiovascular events in statin-naïve patients with acute STEMI, suggesting a potential link between furin cleavage process of PCSK9 and its effect on prognosis. (249 words).
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Affiliation(s)
- Jun Sawaguchi
- Department of Cardiology, 1-1 Daigaku, Uchinada, 920-0293, Japan
| | - Yasuhiko Saeki
- Department of Cardiology, 1-1 Daigaku, Uchinada, 920-0293, Japan
| | - Minako Oda
- Department of Cardiology, 1-1 Daigaku, Uchinada, 920-0293, Japan
| | | | | | - Minoru Wakasa
- Department of Cardiology, 1-1 Daigaku, Uchinada, 920-0293, Japan
| | - Hironobu Akao
- Department of Cardiology, 1-1 Daigaku, Uchinada, 920-0293, Japan
| | - Michihiko Kitayama
- Trans-catheter Cardiovascular Therapeutics, Kanazawa Medical University, 1-1 Daigaku, Uchinada, 920-0293, Japan
| | - Yasuyuki Kawai
- Department of Cardiology, 1-1 Daigaku, Uchinada, 920-0293, Japan
| | - Kouji Kajinami
- Department of Cardiology, 1-1 Daigaku, Uchinada, 920-0293, Japan,Corresponding author. Department of Cardiology, Kanazawa Medical University , 1-1 Daigaku, Uchinada 920-0293, Japan.
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Cimaglia P, Fortini F, Vieceli Dalla Sega F, Cardelli LS, Massafra RF, Morelli C, Trichilo M, Ferrari R, Rizzo P, Campo G. Relationship between PCSK9 and endothelial function in patients with acute myocardial infarction. Nutr Metab Cardiovasc Dis 2022; 32:2105-2111. [PMID: 35915019 DOI: 10.1016/j.numecd.2022.06.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 06/25/2022] [Accepted: 06/28/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND AIMS While the role of PCSK9 in lipid metabolism is well established, its link with endothelial function is less clear. The aim of the present study is to evaluate the relationship between PCSK9 and endothelial dysfunction in the setting of acute myocardial infarction. METHODS AND RESULTS To this purpose, we analyzed the serum of 74 patients with ST-elevation myocardial infarction (STEMI) at the time of admission and after 5 days. Endothelial dysfunction was evaluated as rate of apoptosis (AR) of human umbilical vein endothelial cells incubated with patients' serum. There was a good correlation between PCSK9 and the apoptosis rate values, both at baseline (r = 0.649) and 5-day (r = 0.648). In the 5 days after STEMI, PCSK9 increased significantly (242-327 ng/ml, p < 0.001), while AR did not (p = 0.491). Overall, 21 (28%) patients showed a reduction of PCSK9, and they had a significantly higher decrease of AR as compared to others (-13.87 vs 5.8%, p = 0.002). At the univariable analysis, the 5-day change of PCSK9 resulted to be the only variable associated with the 5-day change of the apoptosis rate (beta 0.217, 95%CI 0.091-0.344, p = 0.001). CONCLUSION The variation of endothelial function and PCKS9 in the first days after an acute myocardial infarction are related. Further validation and research are necessary to confirm our findings. CLINICAL TRIAL NCT02438085.
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Affiliation(s)
- Paolo Cimaglia
- Maria Cecilia Hospital, GVM Care and Research, via Corriera 1, 48033, Cotignola RA, Italy.
| | - Francesca Fortini
- Maria Cecilia Hospital, GVM Care and Research, via Corriera 1, 48033, Cotignola RA, Italy
| | | | - Laura Sofia Cardelli
- Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, via Aldo Moro 8, 44124, Ferrara, Italy
| | | | - Cristina Morelli
- Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, via Aldo Moro 8, 44124, Ferrara, Italy
| | - Michele Trichilo
- Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, via Aldo Moro 8, 44124, Ferrara, Italy
| | - Roberto Ferrari
- Maria Cecilia Hospital, GVM Care and Research, via Corriera 1, 48033, Cotignola RA, Italy
| | - Paola Rizzo
- Maria Cecilia Hospital, GVM Care and Research, via Corriera 1, 48033, Cotignola RA, Italy
| | - Gianluca Campo
- Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, via Aldo Moro 8, 44124, Ferrara, Italy
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Ma Y, Zha L, Zhang Q, Cao L, Zhao R, Ma J, Hou K, Pan Y, Cong H, Li X. Effect of PCSK9 Inhibitor on Contrast-Induced Acute Kidney Injury in Patients with Acute Myocardial Infarction Undergoing Intervention Therapy. Cardiol Res Pract 2022; 2022:1638209. [PMID: 36051574 PMCID: PMC9427281 DOI: 10.1155/2022/1638209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 07/30/2022] [Indexed: 01/13/2023] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to inhibit pyroptosis and apoptosis, which play important roles in the development and progression of contrast-induced acute kidney injury (CI-AKI). However, to the best of our knowledge, no studies have investigated the potential effect of PCSK9 inhibitors on the prevalence of CI-AKI after percutaneous coronary intervention (PCI). This study aimed to determine whether PCSK9 inhibitors are associated with the prevalence of CI-AKI. The medical records of 309 (mean age, 63.35 years; 71.84% male) patients with acute myocardial infarction who underwent PCI at our institution were retrospectively analyzed. Overall, 149 and 160 patients were assigned to the evolocumab and control groups, respectively. Serum creatinine levels were examined preoperatively and 24-72 h postoperatively and compared between groups. Data were grouped according to the occurrence of CI-AKI, and a univariate analysis was conducted to exclude suspected influencing factors that led to CI-AKI occurrence. After adjusting for confounding factors, a logistic regression analysis was performed to assess the association between evolocumab administration (independent variable) and CI-AKI occurrence (dependent variable). The prevalence of CI-AKI was significantly lower in the evolocumab group (6.7%) than in the control group (20.0%; p < 0.01).We further evaluated the correlation between exposure factor and outcome. The relative risk(RR) between the use of evolocumab and the occurrence of CI-AKI was 0.34(95% CI 0.17-0.66,p<0.01).This result indicate a significant association between the use of evolocumab and a reduction in the incidence of CI-AKI.The logistic regression analysis results revealed that evolocumab was significantly associated with CI-AKI. The use of PCSK9 inhibitors, hydration therapy, and statin administration appears promising for preventing CI-AKI in patients with acute myocardial infarction undergoing PCI.
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Affiliation(s)
- Yu Ma
- Department of Cardiology, Tianjin Chest Hospital, Tianjin 300222, China
| | - Lei Zha
- Department of Cardiology, Tianjin Chest Hospital, Tianjin 300222, China
| | - Qi Zhang
- Department of Cardiology, Tianjin Chest Hospital, Tianjin 300222, China
| | - Lu Cao
- Department of Cardiology, Tianjin Chest Hospital, Tianjin 300222, China
| | - Ru Zhao
- Department of Cardiology, Tianjin Chest Hospital, Tianjin 300222, China
| | - Jing Ma
- Tianjin Institute of Cardiovascular Diseases, Tianjin Chest Hospital, Tianjin 300222, China
| | - Kai Hou
- Tianjin Medical University, Tianjin Chest Hospital, Tianjin 300222, China
| | - Yue Pan
- Department of Cardiology, Tianjin Chest Hospital, Tianjin 300222, China
| | - Hongliang Cong
- Department of Cardiology, Tianjin Chest Hospital, Tianjin 300222, China
| | - Ximing Li
- Department of Cardiology, Clinical School of Thoracic, Tianjin Medical University, Jinnan, Tianjin 300222, China
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Inoue Y, Tasaki M, Masuda T, Misumi Y, Nomura T, Ando Y, Ueda M. α-Enolase reduces cerebrovascular Aβ deposits by protecting Aβ amyloid formation. Cell Mol Life Sci 2022; 79:462. [PMID: 35916996 PMCID: PMC11072596 DOI: 10.1007/s00018-022-04493-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 06/29/2022] [Accepted: 07/17/2022] [Indexed: 11/03/2022]
Abstract
Cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid β (Aβ) deposits and causes dementia and cerebral hemorrhage. Although α-enolase (ENO1) was shown to possess multifunctional roles, its exact functions in CAA pathogenesis have not been determined. In this study, we focused on ENO1, a well-known glycolytic enzyme, which was previously identified via a proteomic approach as an upregulated protein in brain samples from patients with Alzheimer's disease (AD). We utilized the thioflavin T fluorescence assay and transmission electron microscopy to monitor the effects of ENO1 on amyloid formation by Aβ peptides. We also cultured murine primary cerebrovascular smooth muscle cells to determine the effects of ENO1 on Aβ cytotoxicity. To investigate the effects of ENO1 in vivo, we infused ENO1 or a vehicle control into the brains of APP23 mice, a transgenic model of AD/CAA, using a continuous infusion system, followed by a cognitive test and pathological and biochemical analyses. We found that novel functions of ENO1 included interacting with Aβ and inhibiting its fibril formation, disrupting Aβ fibrils, and weakening the cytotoxic effects of these fibrils via proteolytic degradation of Aβ peptide. We also demonstrated that infusion of ENO1 into APP23 mouse brains reduced cerebrovascular Aβ deposits and improved cognitive impairment. In addition, we found that enzymatically inactivated ENO1 failed to inhibit Aβ fibril formation and fibril disruption. The proteolytic activity of ENO1 may thus underlie the enzyme's cytoprotective effect and clearance of Aβ from the brain, and ENO1 may be a therapeutic target in CAA.
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Affiliation(s)
- Yasuteru Inoue
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Chuo-ku, Honjo, Kumamoto, Kumamoto, 860-8556, Japan.
| | - Masayoshi Tasaki
- Department of Biomedical Laboratory Sciences, Graduate School of Health Sciences, Kumamoto University, Kumamoto, Japan
| | - Teruaki Masuda
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Chuo-ku, Honjo, Kumamoto, Kumamoto, 860-8556, Japan
| | - Yohei Misumi
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Chuo-ku, Honjo, Kumamoto, Kumamoto, 860-8556, Japan
| | - Toshiya Nomura
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Chuo-ku, Honjo, Kumamoto, Kumamoto, 860-8556, Japan
| | - Yukio Ando
- Department of Amyloidosis Research, Nagasaki International University, Sasebo, Japan
| | - Mitsuharu Ueda
- Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Chuo-ku, Honjo, Kumamoto, Kumamoto, 860-8556, Japan
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The role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the pathophysiology of psoriasis and systemic lupus erythematosus. Postepy Dermatol Alergol 2022; 39:645-650. [PMID: 36090718 PMCID: PMC9454343 DOI: 10.5114/ada.2022.118919] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 04/01/2021] [Indexed: 11/29/2022] Open
Abstract
Inflammation and atherogenic dyslipidaemia are often observed in skin diseases and represent an increased risk of cardiovascular disorders. Proprotein convertase subtilisin/kexin type 9 plays an important role in the regulation of serum low-density lipoprotein cholesterol levels. Its biological role, however, seems to go much beyond the regulation of cholesterol metabolism. The article presents potential pathophysiological links between inflammatory process and lipid disorders based on the example of psoriasis and systemic lupus erythematosus.
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Paron F, Barattucci S, Cappelli S, Romano M, Berlingieri C, Stuani C, Laurents D, Mompeán M, Buratti E. Unravelling the toxic effects mediated by the neurodegenerative disease-associated S375G mutation of TDP-43 and its S375E phosphomimetic variant. J Biol Chem 2022; 298:102252. [PMID: 35835219 PMCID: PMC9364110 DOI: 10.1016/j.jbc.2022.102252] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 06/23/2022] [Accepted: 06/25/2022] [Indexed: 12/05/2022] Open
Abstract
TAR DNA-binding protein 43 (TDP-43) is a nucleic acid–binding protein found in the nucleus that accumulates in the cytoplasm under pathological conditions, leading to proteinopathies, such as frontotemporal dementia and ALS. An emerging area of TDP-43 research is represented by the study of its post-translational modifications, the way they are connected to disease-associated mutations, and what this means for pathological processes. Recently, we described a novel mutation in TDP-43 in an early onset ALS case that was affecting a potential phosphorylation site in position 375 (S375G). A preliminary characterization showed that both the S375G mutation and its phosphomimetic variant, S375E, displayed altered nuclear–cytoplasmic distribution and cellular toxicity. To better investigate these effects, here we established cell lines expressing inducible WT, S375G, and S375E TDP-43 variants. Interestingly, we found that these mutants do not seem to affect well-studied aspects of TDP-43, such as RNA splicing or autoregulation, or protein conformation, dynamics, or aggregation, although they do display dysmorphic nuclear shape and cell cycle alterations. In addition, RNA-Seq analysis of these cell lines showed that although the disease-associated S375G mutation and its phosphomimetic S375E variant regulate distinct sets of genes, they have a common target in mitochondrial apoptotic genes. Taken together, our data strongly support the growing evidence that alterations in TDP-43 post-translational modifications can play a potentially important role in disease pathogenesis and provide a further link between TDP-43 pathology and mitochondrial health.
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Affiliation(s)
- Francesca Paron
- Molecular Pathology, International Centre for Genetic and Engineering Biotechnology (ICGEB), Trieste, Italy
| | - Simone Barattucci
- Molecular Pathology, International Centre for Genetic and Engineering Biotechnology (ICGEB), Trieste, Italy
| | - Sara Cappelli
- Molecular Pathology, International Centre for Genetic and Engineering Biotechnology (ICGEB), Trieste, Italy
| | - Maurizio Romano
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Christian Berlingieri
- Molecular Pathology, International Centre for Genetic and Engineering Biotechnology (ICGEB), Trieste, Italy
| | - Cristiana Stuani
- Molecular Pathology, International Centre for Genetic and Engineering Biotechnology (ICGEB), Trieste, Italy
| | - Douglas Laurents
- "Rocasolano" Institute for Physical Chemistry, Spanish National Research Council, Serrano 119, 28006, Madrid, Spain
| | - Miguel Mompeán
- "Rocasolano" Institute for Physical Chemistry, Spanish National Research Council, Serrano 119, 28006, Madrid, Spain
| | - Emanuele Buratti
- Molecular Pathology, International Centre for Genetic and Engineering Biotechnology (ICGEB), Trieste, Italy.
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Cai YJ, Li PH, Wang XA, Xu YM, Yang S, Tang YN, Zhu Z, Yang XY, He JY, Luo H, Zhang T, Qi H, Chen X, Qin QW, Sun HY. Epinephelus coioides PCSK9 affect the infection of SGIV by regulating the innate immune response. FISH & SHELLFISH IMMUNOLOGY 2022; 126:113-121. [PMID: 35609761 DOI: 10.1016/j.fsi.2022.05.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Revised: 05/16/2022] [Accepted: 05/18/2022] [Indexed: 06/15/2023]
Abstract
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) in mammals is a multifunctional protein. In this study, PCSK9 of marine fish Epinephelus coioides was characterized. The full-length cDNA of E. coioides PCSK9 was 2458 bp in length containing 185 bp 5' UTR, 263 bp 3' UTR and 2010 bp open reading frame (ORF) encoding 669 amino acids with the predicted molecular weight of 71 kDa and the theoretical PI of 6.6. Similar to other members of PCSK9 family, E. coioides PCSK9 has three conserved domains: Inhibitor_ I9 super family, Peptidases_ S8_ PCSK9_ Proteinase K_ like, and PCSK9_ C-CRD super family. E. coioides PCSK9 mRNA could be detected in all the tissues examined by real-time quantitative PCR, with the highest expression in the brain, followed by skin, trunk kidney, head kidney, intestine, blood, liver, spleen, gill, muscle and heart. E. coioides PCSK9 was distributed in both the cytoplasm and nucleus. The expression of E. coioides PCSK9 was significantly upregulated during Singapore grouper iridovirus (SGIV) infection. Upregulated PCSK9 could significantly affect the activities of nuclear factor kappaB (NF-κB) promoter, SGIV-induced apoptosis, and the expressions of the key SGIV genes (ICP18, LITAT, MCP, and VP19) and the E. coioides proinflammatory factors (IL-6, IL-1β, IL-8, and TNF-α). The results illustrated that E. coioides PCSK9 might be involved in the pathogen infection by regulating the innate immune response.
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Affiliation(s)
- Yi-Jie Cai
- University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Pin-Hong Li
- University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Xiao-Ai Wang
- University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Yu-Min Xu
- University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Shan Yang
- University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Yan-Na Tang
- University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Zheng Zhu
- University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Xin-Yue Yang
- University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Jia-Yang He
- University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Hao Luo
- University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Tong Zhang
- University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Hong Qi
- University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China
| | - Xiao Chen
- University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China.
| | - Qi-Wei Qin
- University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China; Southern Marine Science and Engineering Guangdong Laboratory, Zhuhai, 519000, PR China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266000, PR China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, PR China.
| | - Hong-Yan Sun
- University Joint Laboratory of Guangdong Province, Hong Kong and Macao Region on Marine Bioresource Conservation and Exploitation, Guangdong Laboratory for Lingnan Modern Agriculture, College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, Guangdong Province, PR China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, 510642, PR China.
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Yang T, Datsomor O, Jiang M, Ma X, Zhao G, Zhan K. Protective Roles of Sodium Butyrate in Lipopolysaccharide-Induced Bovine Ruminal Epithelial Cells by Activating G Protein-Coupled Receptors 41. Front Nutr 2022; 9:842634. [PMID: 35600833 PMCID: PMC9121101 DOI: 10.3389/fnut.2022.842634] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 03/10/2022] [Indexed: 11/13/2022] Open
Abstract
This study aimed to evaluate whether sodium butyrate (SB) attenuates the ruminal response to LPS-stimulated inflammation by activating GPR41 in bovine rumen epithelial cells (BRECs). We examined the SB regulation of GPR41 and its impact on LPS-induced inflammation using GPR41 knockdown BRECs. The LPS-induced BRECs showed increases in the expression of genes related to pro-inflammation and decreases in the expression of genes related to tight junction proteins; these were attenuated by pretreatment with SB. Compared with that in LPS-stimulated BRECs, the ratio of phosphorylated NF-κB (p65 subunit) to NF-κB (p65 subunit) and the ratio of phosphorylated IκBα to IκBα were suppressed with SB pretreatment. The LSB group abated LPS-induced apoptosis and decreased the expression of Bax, Caspase 3, and Caspase 9 mRNA relative to the LPS group. In addition, the LSB group had a lower proportion of cells in the G0–G1 phase and a higher proportion of cells in the S phase than the LPS group. The mRNA expression of ACAT1 and BDH1 genes related to volatile fatty acid (VFA) metabolism were upregulated in the LSB group compared to those in LPS-induced BRECs. In addition, pretreatment with SB promoted the gene expression of GPR41 in the LPS-induced BRECs. Interestingly, SB pretreatment protected BRECs but not GPR41KD BRECs. Our results suggest that SB pretreatment protects against the changes in BRECs LPS-induced inflammatory response by activating GPR41.
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Li L, Liu S, Tan J, Wei L, Wu D, Gao S, Weng Y, Chen J. Recent advance in treatment of atherosclerosis: Key targets and plaque-positioned delivery strategies. J Tissue Eng 2022; 13:20417314221088509. [PMID: 35356091 PMCID: PMC8958685 DOI: 10.1177/20417314221088509] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Atherosclerosis, a chronic inflammatory disease of vascular wall, is a progressive pathophysiological process with lipids oxidation/depositing initiation and innate/adaptive immune responses. The coordination of multi systems covering oxidative stress, dysfunctional endothelium, diseased lipid uptake, cell apoptosis, thrombotic and pro-inflammatory responding as well as switched SMCs contributes to plaque growth. In this circumstance, inevitably, targeting these processes is considered to be effective for treating atherosclerosis. Arriving, retention and working of payload candidates mediated by targets in lesion direct ultimate therapeutic outcomes. Accumulating a series of scientific studies and clinical practice in the past decades, lesion homing delivery strategies including stent/balloon/nanoparticle-based transportation worked as the potent promotor to ensure a therapeutic effect. The objective of this review is to achieve a very brief summary about the effective therapeutic methods cooperating specifical targets and positioning-delivery strategies in atherosclerosis for better outcomes.
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Affiliation(s)
- Li Li
- Key Laboratory of Advanced Technology of Materials, Ministry of Education, Southwest Jiaotong University, Chengdu, PR China
| | - Sainan Liu
- Key Laboratory of Advanced Technology of Materials, Ministry of Education, Southwest Jiaotong University, Chengdu, PR China
| | - Jianying Tan
- Key Laboratory of Advanced Technology of Materials, Ministry of Education, Southwest Jiaotong University, Chengdu, PR China
| | - Lai Wei
- Key Laboratory of Advanced Technology of Materials, Ministry of Education, Southwest Jiaotong University, Chengdu, PR China
| | - Dimeng Wu
- Chengdu Daxan Innovative Medical Tech. Co., Ltd., Chengdu, PR China
| | - Shuai Gao
- Chengdu Daxan Innovative Medical Tech. Co., Ltd., Chengdu, PR China
| | - Yajun Weng
- Key Laboratory of Advanced Technology of Materials, Ministry of Education, Southwest Jiaotong University, Chengdu, PR China
| | - Junying Chen
- Key Laboratory of Advanced Technology of Materials, Ministry of Education, Southwest Jiaotong University, Chengdu, PR China
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Maligłówka M, Kosowski M, Hachuła M, Cyrnek M, Bułdak Ł, Basiak M, Bołdys A, Machnik G, Bułdak RJ, Okopień B. Insight into the Evolving Role of PCSK9. Metabolites 2022; 12:metabo12030256. [PMID: 35323699 PMCID: PMC8951079 DOI: 10.3390/metabo12030256] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 03/12/2022] [Accepted: 03/15/2022] [Indexed: 02/04/2023] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the last discovered member of the family of proprotein convertases (PCs), mainly synthetized in hepatic cells. This serine protease plays a pivotal role in the reduction of the number of low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes, which leads to an increase in the level of cholesterol in the blood. This mechanism and the fact that gain of function (GOF) mutations in PCSK9 are responsible for causing familial hypercholesterolemia whereas loss-of-function (LOF) mutations are associated with hypocholesterolemia, prompted the invention of drugs that block PCSK9 action. The high efficiency of PCSK9 inhibitors (e.g., alirocumab, evolocumab) in decreasing cardiovascular risk, pleiotropic effects of other lipid-lowering drugs (e.g., statins) and the multifunctional character of other proprotein convertases, were the cause for proceeding studies on functions of PCSK9 beyond cholesterol metabolism. In this article, we summarize the current knowledge on the roles that PCSK9 plays in different tissues and perspectives for its clinical use.
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Affiliation(s)
- Mateusz Maligłówka
- Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia in Katowice, 40-007 Katowice, Poland; (M.K.); (M.H.); (M.C.); (Ł.B.); (M.B.); (A.B.); (G.M.); (B.O.)
- Correspondence:
| | - Michał Kosowski
- Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia in Katowice, 40-007 Katowice, Poland; (M.K.); (M.H.); (M.C.); (Ł.B.); (M.B.); (A.B.); (G.M.); (B.O.)
| | - Marcin Hachuła
- Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia in Katowice, 40-007 Katowice, Poland; (M.K.); (M.H.); (M.C.); (Ł.B.); (M.B.); (A.B.); (G.M.); (B.O.)
| | - Marcin Cyrnek
- Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia in Katowice, 40-007 Katowice, Poland; (M.K.); (M.H.); (M.C.); (Ł.B.); (M.B.); (A.B.); (G.M.); (B.O.)
| | - Łukasz Bułdak
- Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia in Katowice, 40-007 Katowice, Poland; (M.K.); (M.H.); (M.C.); (Ł.B.); (M.B.); (A.B.); (G.M.); (B.O.)
| | - Marcin Basiak
- Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia in Katowice, 40-007 Katowice, Poland; (M.K.); (M.H.); (M.C.); (Ł.B.); (M.B.); (A.B.); (G.M.); (B.O.)
| | - Aleksandra Bołdys
- Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia in Katowice, 40-007 Katowice, Poland; (M.K.); (M.H.); (M.C.); (Ł.B.); (M.B.); (A.B.); (G.M.); (B.O.)
| | - Grzegorz Machnik
- Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia in Katowice, 40-007 Katowice, Poland; (M.K.); (M.H.); (M.C.); (Ł.B.); (M.B.); (A.B.); (G.M.); (B.O.)
| | - Rafał Jakub Bułdak
- Institute of Medical Sciences, University of Opole, 45-040 Opole, Poland;
| | - Bogusław Okopień
- Department of Internal Medicine and Clinical Pharmacology, School of Medicine in Katowice, Medical University of Silesia in Katowice, 40-007 Katowice, Poland; (M.K.); (M.H.); (M.C.); (Ł.B.); (M.B.); (A.B.); (G.M.); (B.O.)
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Lin X, Ouyang S, Zhi C, Li P, Tan X, Ma W, Yu J, Peng T, Chen X, Li L, Xie W. Focus on ferroptosis, pyroptosis, apoptosis and autophagy of vascular endothelial cells to the strategic targets for the treatment of atherosclerosis. Arch Biochem Biophys 2022; 715:109098. [PMID: 34856194 DOI: 10.1016/j.abb.2021.109098] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 11/15/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023]
Abstract
Vascular endothelial cells (VECs), which are lined up in the inner surface of blood vessels, are in direct contact with the metabolite-related endogenous danger signals in the circulatory system. Moreover, VECs death impairs vasodilation and increases endothelium-dependent permeability, which is strongly correlated with the development of atherosclerosis (AS). Among several forms of cell death, regulatory death of endothelial cells frequently occurs in AS, mainly including ferroptosis, pyroptosis, apoptosis and autophagy. In this review, we summarize regulatory factors and signaling mechanisms of regulatory death in endothelial cells, discussing their effects in the context of the atherosclerotic procession.
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Affiliation(s)
- Xiaoyan Lin
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, Hunan, China
| | - Siyu Ouyang
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, 421001, Hunan, China
| | - Chenxi Zhi
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, 421001, Hunan, China
| | - Pin Li
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, 421001, Hunan, China
| | - Xiaoqian Tan
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, 421001, Hunan, China
| | - Wentao Ma
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, 421001, Hunan, China
| | - Jiang Yu
- 2019 Class of Clinical Medicine, University of South China, Hengyang, 421001, Hunan, China
| | - Tianhong Peng
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, 421001, Hunan, China
| | - Xi Chen
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, 421001, Hunan, China
| | - Liang Li
- Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Medical Research Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, Hunan, China; School of Public Health, University of South China, Hengyang, 421001, Hunan, China.
| | - Wei Xie
- Clinical Anatomy & Reproductive Medicine Application Institute, University of South China, Hengyang, 421001, Hunan, China.
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Yu Q, Liu R, Chen Y, Waqar AB, Liu F, Yang J, Lian T, Zhang G, Guan H, Cui Y, Xu C. Discoidin Domain-Containing Receptor 2 Is Present in Human Atherosclerotic Plaques and Involved in the Expression and Activity of MMP-2. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:1010496. [PMID: 34956435 PMCID: PMC8702333 DOI: 10.1155/2021/1010496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 11/30/2021] [Indexed: 11/17/2022]
Abstract
Discoidin domain-containing receptor 2 (DDR2) has been suggested to be involved in atherosclerotic progression, but its pathological role remains unknown. Using immunochemical staining, we located and compared the expression of DDR2 in the atherosclerotic plaques of humans and various animal models. Then, siRNA was applied to knock down the expression of DDR2 in vascular smooth muscle cells (VSMCs), and the migration, proliferation, and collagen Ι-induced expression of matrix metalloproteinases (MMPs) were evaluated. We found that an abundance of DDR2 was present in the atherosclerotic plaques of humans and various animal models and was distributed around fatty and necrotic cores. After incubation of oxidized low-density lipoprotein (ox-LDL), DDR2 was upregulated in VSMCs in response to such a proatherosclerotic condition. Next, we found that decreased DDR2 expression in VSMCs inhibited the migration, proliferation, and collagen Ι-induced expression of matrix metalloproteinases (MMPs). Moreover, we found that DDR2 is strongly associated with the protein expression and activity of MMP-2, suggesting that DDR2 might play a role in the etiology of unstable plaques. Considering that DDR2 is present in the atherosclerotic plaques of humans and is associated with collagen Ι-induced secretion of MMP-2, the clinical role of DDR2 in cardiovascular disease should be elucidated in further experiments.
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Affiliation(s)
- Qi Yu
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Shaanxi Key Laboratory of Brain Disorders, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China
- Department of Histology and Embryology, Xi'an Medical University, Xi'an 710021, China
| | - Ruihan Liu
- Department of Pathology, Zhengzhou Central Hospital, Zhengzhou 450007, China
| | - Ying Chen
- School of Computer Science and Technology, Xi'an University of Posts and Telecommunications, Xi'an 710121, China
| | - Ahmed Bilal Waqar
- Faculty of Allied and Health Sciences, Imperial College of Business Studies, Lahore, Pakistan
| | - Fuqiang Liu
- Cardiovascular Department, Shaanxi Provincial People's Hospital, Xi'an 710010, China
| | - Juan Yang
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Shaanxi Key Laboratory of Brain Disorders, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China
| | - Ting Lian
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Shaanxi Key Laboratory of Brain Disorders, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China
| | - Guangwei Zhang
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Shaanxi Key Laboratory of Brain Disorders, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China
| | - Hua Guan
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Shaanxi Key Laboratory of Brain Disorders, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China
| | - Yuanyuan Cui
- Department of Histology and Embryology, Xi'an Medical University, Xi'an 710021, China
| | - Cangbao Xu
- Shaanxi Key Laboratory of Ischemic Cardiovascular Diseases & Shaanxi Key Laboratory of Brain Disorders, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, China
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Marques P, Domingo E, Rubio A, Martinez-Hervás S, Ascaso JF, Piqueras L, Real JT, Sanz MJ. Beneficial effects of PCSK9 inhibition with alirocumab in familial hypercholesterolemia involve modulation of new immune players. Biomed Pharmacother 2021; 145:112460. [PMID: 34864314 DOI: 10.1016/j.biopha.2021.112460] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 11/11/2021] [Accepted: 11/19/2021] [Indexed: 12/27/2022] Open
Abstract
Familial hypercholesterolemia (FH) is associated with low-grade systemic inflammation, a key driver of premature atherosclerosis. We investigated the effects of inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) function on inflammatory state, endothelial dysfunction and cardiovascular outcomes in patients with FH. Fourteen patients with FH were evaluated before and 8 weeks after administration of a PCSK9 blocking monoclonal antibody (alirocumab, 150 mg/subcutaneous/14 days). In vivo and ex vivo analysis revealed that alirocumab blunted the attachment of leukocytes to TNFα-stimulated human umbilical arterial endothelial cells (HUAEC) and suppressed the activation of platelets and most leukocyte subsets, which was accompanied by the diminished expression of CX3CR1, CXCR6 and CCR2 on several leukocyte subpopulations. By contrast, T-regulatory cell activation was enhanced by alirocumab treatment, which also elevated anti-inflammatory IL-10 plasma levels and lowered circulating pro-inflammatory cytokines. Plasma levels of IFNγ positively correlated with levels of total and LDL-cholesterol, whereas circulating IL-10 levels negatively correlated with these key lipid parameters. In vitro analysis revealed that TNFα stimulation of HUAEC increased the expression of PCSK9, whereas endothelial PCSK9 silencing reduced TNFα-induced mononuclear cell adhesion mediated by Nox5 up-regulation and p38-MAPK/NFκB activation, concomitant with reduced SREBP2 expression. PCSK9 silencing also decreased endothelial CX3CL1 and CXCL16 expression and chemokine generation. In conclusion, PCSK9 inhibition impairs systemic inflammation and endothelial dysfunction by constraining leukocyte-endothelium interactions. PCSK9 blockade may constitute a new therapeutic approach to control the inflammatory state associated with FH, preventing further cardiovascular events in this cardiometabolic disorder.
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Affiliation(s)
- Patrice Marques
- Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain; Institute of Health Research INCLIVA, Av. Menéndez Pelayo 4, 46010 Valencia, Spain
| | - Elena Domingo
- Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain
| | - Arantxa Rubio
- Endocrinology and Nutrition Service, University Clinic Hospital of Valencia, Av. Blasco Ibañez 17, 46010 Valencia, Spain
| | - Sergio Martinez-Hervás
- Department of Medicine, Faculty of Medicine and Odontology, University of Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain; Institute of Health Research INCLIVA, Av. Menéndez Pelayo 4, 46010 Valencia, Spain; Endocrinology and Nutrition Service, University Clinic Hospital of Valencia, Av. Blasco Ibañez 17, 46010 Valencia, Spain; CIBERDEM-Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, ISCIII, Av. Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Juan F Ascaso
- Department of Medicine, Faculty of Medicine and Odontology, University of Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain; Institute of Health Research INCLIVA, Av. Menéndez Pelayo 4, 46010 Valencia, Spain; Endocrinology and Nutrition Service, University Clinic Hospital of Valencia, Av. Blasco Ibañez 17, 46010 Valencia, Spain; CIBERDEM-Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, ISCIII, Av. Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Laura Piqueras
- Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain; Institute of Health Research INCLIVA, Av. Menéndez Pelayo 4, 46010 Valencia, Spain; CIBERDEM-Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, ISCIII, Av. Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - José T Real
- Department of Medicine, Faculty of Medicine and Odontology, University of Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain; Institute of Health Research INCLIVA, Av. Menéndez Pelayo 4, 46010 Valencia, Spain; Endocrinology and Nutrition Service, University Clinic Hospital of Valencia, Av. Blasco Ibañez 17, 46010 Valencia, Spain; CIBERDEM-Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, ISCIII, Av. Monforte de Lemos 3-5, 28029 Madrid, Spain.
| | - Maria-Jesus Sanz
- Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain; Institute of Health Research INCLIVA, Av. Menéndez Pelayo 4, 46010 Valencia, Spain; CIBERDEM-Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders, ISCIII, Av. Monforte de Lemos 3-5, 28029 Madrid, Spain.
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Song X, Meng J, Yan G, Wang H, Li H, Lou D. Semaphorin 7A knockdown improves injury and prevents endothelial-to-mesenchymal transition in ox-LDL-induced HUVECs by regulating β1 integrin expression. Exp Ther Med 2021; 22:1441. [PMID: 34721683 PMCID: PMC8549106 DOI: 10.3892/etm.2021.10876] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 07/30/2021] [Indexed: 12/12/2022] Open
Abstract
Atherosclerosis is the most common cause of cardiovascular disease and is accompanied by high mortality rates and a poor prognosis. Semaphorin 7A (Sema7A) and its receptor β1 integrin have been reported to participate in the development of atherosclerosis. However, the role of Sema7A and β1 integrin in endothelial cell injury and endothelial-to-mesenchymal transition (EMT) in atherosclerosis remains undetermined, to the best of our knowledge. The mRNA and protein expression levels of Sema7A and β1 integrin in HUVECs were analyzed using reverse transcription-quantitative PCR (RT-qPCR) and western blot analyses, respectively. HUVECs were induced with 50 µg/ml oxidized low-density lipoprotein (ox-LDL) to establish an atherosclerosis cell model. Cell viability was measured using Cell Counting Kit-8 assay and the production of IL-1β, IL-6 and C-C motif chemokine ligand 2 was determined using ELISA. The expression levels of cell adhesion factors, intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 were analyzed using RT-qPCR and western blot analyses. Cell apoptosis was detected using flow cytometry and western blotting. The levels of EMT-related markers were evaluated using RT-qPCR, western blotting and immunofluorescence staining. The results of the present study revealed that the expression levels of Sema7A and β1 integrin were significantly upregulated in ox-LDL-treated HUVECs. Treatment with ox-LDL significantly decreased cell viability, and increased the levels of inflammatory and adhesion factors, the cell apoptotic rate and the expression levels of EMT-related proteins. Knockdown of Sema7A reversed the ox-LDL-induced inflammatory responses and EMT, while the overexpression of β1 integrin reversed the Sema7A-mediated inhibitory effects on ox-LDL-treated HUVECs. In conclusion, the findings of the present study indicated that Sema7A and β1 integrin may play significant roles in atherosclerosis by mediating endothelial cell injury and EMT progression.
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Affiliation(s)
- Xiaoying Song
- Department of Geriatrics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Jing Meng
- Department of Geriatrics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Guoliang Yan
- Emergency Department, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Haihui Wang
- Emergency Department, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Haitao Li
- Emergency Department, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
| | - Danfei Lou
- Department of Geriatrics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
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Efficacy and Safety of PCSK9 Inhibitors in Stroke Prevention. J Stroke Cerebrovasc Dis 2021; 30:106057. [PMID: 34450482 DOI: 10.1016/j.jstrokecerebrovasdis.2021.106057] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 08/09/2021] [Indexed: 12/19/2022] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) interacts with the low-density lipoprotein (LDL) receptor and, by enhancing its degradation, has a pivotal role in the regulation of cholesterol homeostasis. Two fully humanized monoclonal antibodies targeting PCSK9, evolocumab and alirocumab, are available for clinical use. PCSK9 inhibitors reduce LDL-C 30% more than ezetimibe and 60% more than placebo when added to statins. This reduction in LDL-C is accompanied by a decrease in the risk of major cardiovascular and cerebrovascular events. However, questions have been raised in relation to the cost-effectiveness of these medications. In this article, we review the clinical evidence on the use of PCSK9 inhibitors in lowering LDL-C and their effect on cerebrovascular health.
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Proprotein convertase subtilisin/kexin Type 9 is required for Ahnak-mediated metastasis of melanoma into lung epithelial cells. Neoplasia 2021; 23:993-1001. [PMID: 34352405 PMCID: PMC8350332 DOI: 10.1016/j.neo.2021.07.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 07/17/2021] [Accepted: 07/19/2021] [Indexed: 11/22/2022]
Abstract
Previously we demonstrated that Ahnak mediates transforming growth factor-β (TGFβ)-induced epithelial-mesenchymal transition (EMT) during tumor metastasis. It is well-known that circulating tumor cells (CTCs) invade the vasculature of adjacent target tissues before working to adapt to the host environments. Currently, the molecular mechanism by which infiltrated tumor cells interact with host cells to survive within target tissue environments is far from clear. Here, we show that Ahnak regulates tumor metastasis through PCSK9 expression. To validate the molecular function of Ahnak in metastasis, B16F10 melanoma cells were injected into WT and Ahnak knockout (Ahnak-/-) mice. Ahnak-/- mice were more resistant to the pulmonary metastasis of B16F10 cells compared to wild-type (WT) mice. To investigate the host function of Ahnak in recipient organs against metastasis of melanoma cells, transcriptomic analyses of primary pulmonary endothelial cells from WT or Ahnak-/- mice in the absence or presence of TGFβ stimulation were performed. We found PCSK9, along with several other candidate genes, was involved in the invasion of melanoma cells into lung tissues. PCSK9 expression in the pulmonary artery was higher in WT mice than Ahnak-/- mice. To evaluate the host function of PCSK9 in lung tissues during the metastasis of melanoma cells, we established lung epithelial cell-specific tamoxifen-induced PCSK9 conditional KO mice (Scgb1a1-Cre/PCSK9fl/fl). The pulmonary metastasis of B16F10 cells in Scgb1a1-Cre/PCSK9fl/fl mice was significantly suppressed, indicating that PCSK9 plays an important role in the metastasis of melanoma cells. Taken together, our data demonstrate that Ahnak regulates metastatic colonization through the regulation of PCSK9 expression.
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Xu Q, Li YC, Du C, Wang LN, Xiao YH. Effects of Apigenin on the Expression of LOX-1, Bcl-2, and Bax in Hyperlipidemia Rats. Chem Biodivers 2021; 18:e2100049. [PMID: 34118114 DOI: 10.1002/cbdv.202100049] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 06/11/2021] [Indexed: 12/29/2022]
Abstract
We aimed to investigate the impact of apigenin on LOX-1, Bcl-2, and Bax expression in hyperlipidemia rats and explore the possible molecular pathological mechanism of apigenin in improving hyperlipidemia and preventing atherosclerosis. In hyperlipidemia models, the levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c) and the LOX-1 protein expression were apparently increased (P<0.01), while the high-density lipoprotein cholesterol (HDL-c) levels and the ratio of Bcl-2/Bax were reduced significantly (P<0.01) in comparison with the standard control group. After the treatment of apigenin, the levels of TC, TG, LDL-c, and the LOX-1 protein expression were noticeably decreased (P<0.01), while the levels of HDL-c and the Bcl-2/Bax ratio were increased (P<0.01). The intima was thickened and had protrusions in the hyperlipidemia model group compared to the normal control group. In comparison with the atherosclerosis model group, the degree of aortic lesions in the low-dose, middle-dose, high-dose groups was alleviated. Apigenin can reduce the level of blood lipid, improve hyperlipidemia, and prevent atherosclerosis in hyperlipidemia rats. The molecular mechanism may be related to inhibiting LOX-1 gene expression and increasing the Bcl-2/Bax ratio.
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Affiliation(s)
- Qian Xu
- Department of Biochemistry, Chengde Medical University, Chengde, 067000, P. R. China
| | - Yan-Chao Li
- Department of Biochemistry, Chengde Medical University, Chengde, 067000, P. R. China
| | - Chao Du
- Department of Biochemistry, Chengde Medical University, Chengde, 067000, P. R. China
| | - Li-Na Wang
- Department of Biochemistry, Chengde Medical University, Chengde, 067000, P. R. China
| | - Yan-Hong Xiao
- Department of Biochemistry, Chengde Medical University, Chengde, 067000, P. R. China
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Maligłówka M, Bułdak Ł, Okopień B, Bołdys A. The consequences of PCSK9 inhibition in selected tissues. POSTEP HIG MED DOSW 2021. [DOI: 10.5604/01.3001.0014.9127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of nine members of the proprotein
convertase family. These serine proteases play a pivotal role in the post-translational
modification of proteins and the activation of hormones, enzymes, transcription factors and
growth factors. As a result, they participate in many physiological processes like embryogenesis,
activity of central nervous system and lipid metabolism. Scientific studies show
that the family of convertases is also involved in the pathogenesis of viral and bacterial
infections, osteoporosis, hyperglycaemia, cardiovascular diseases, neurodegenerative disorders
and cancer. The inhibition of PCSK9 by two currently approved for use monoclonal
antibodies (alirocumab, evolocumab) slows down the degradation of low-density lipoprotein
cholesterol receptors (LDLRs). This leads to increased density of LDLRs on the surface
of hepatocytes, resulting in decreased level of low-density lipoprotein cholesterol (LDL-C)
in the bloodstream, which is connected with the reduction of cardiovascular risk. PCSK9 inhibitors (PCSK9i) were created for the patients who could not achieve appropriate level
of LDL-C using current statin and ezetimibe therapy. It seems that high therapeutic efficacy
of PCSK9i will make them more common in the clinical use. The pleiotropic effects
of previously mentioned lipid-lowering therapies were the reasons for literature review of
possible positive and negative effects of PCSK9 inhibition beyond cholesterol metabolism.
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Affiliation(s)
- Mateusz Maligłówka
- Katedra Farmakologii, Klinika Chorób Wewnętrznych i Farmakologii Klinicznej, Wydział Nauk Medycznych Śląskiego Uniwersytetu Medycznego w Katowicach
| | - Łukasz Bułdak
- Katedra Farmakologii, Klinika Chorób Wewnętrznych i Farmakologii Klinicznej, Wydział Nauk Medycznych Śląskiego Uniwersytetu Medycznego w Katowicach
| | - Bogusław Okopień
- Katedra Farmakologii, Klinika Chorób Wewnętrznych i Farmakologii Klinicznej, Wydział Nauk Medycznych Śląskiego Uniwersytetu Medycznego w Katowicach
| | - Aleksandra Bołdys
- Katedra Farmakologii, Klinika Chorób Wewnętrznych i Farmakologii Klinicznej, Wydział Nauk Medycznych Śląskiego Uniwersytetu Medycznego w Katowicach
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Ragusa R, Basta G, Neglia D, De Caterina R, Del Turco S, Caselli C. PCSK9 and atherosclerosis: Looking beyond LDL regulation. Eur J Clin Invest 2021; 51:e13459. [PMID: 33236356 DOI: 10.1111/eci.13459] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/03/2020] [Accepted: 11/21/2020] [Indexed: 12/14/2022]
Abstract
Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is involved in cholesterol homeostasis. After binding to the complex low-density lipoprotein (LDL)-receptor, PCSK9 induces its intracellular degradation, thus reducing serum LDL clearance. In addition to the well-known activity on the hepatic LDL receptor-mediated pathway, PCSK9 has been, however, associated with vascular inflammation in atherogenesis. Indeed, PCSK9 is expressed by various cell types that are involved in atherosclerosis (e.g. endothelial cells, smooth muscle cells and macrophages) and is detected inside human atherosclerotic plaques. We here analyse the biology of PCSK9 and its possible involvement in molecular processes involved in atherosclerosis, beyond the regulation of circulating LDL cholesterol levels.
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Affiliation(s)
- Rosetta Ragusa
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.,Institute of Clinical Physiology, CNR, Pisa, Italy
| | | | - Danilo Neglia
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.,Institute of Clinical Physiology, CNR, Pisa, Italy.,Fondazione Toscana G. Monasterio, Pisa, Italy
| | - Raffaele De Caterina
- Fondazione Toscana G. Monasterio, Pisa, Italy.,Cardiovascular Division, Pisa University Hospital, University of Pisa, Pisa, Italy
| | | | - Chiara Caselli
- Institute of Clinical Physiology, CNR, Pisa, Italy.,Fondazione Toscana G. Monasterio, Pisa, Italy
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47
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Luquero A, Badimon L, Borrell-Pages M. PCSK9 Functions in Atherosclerosis Are Not Limited to Plasmatic LDL-Cholesterol Regulation. Front Cardiovasc Med 2021; 8:639727. [PMID: 33834043 PMCID: PMC8021767 DOI: 10.3389/fcvm.2021.639727] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 03/01/2021] [Indexed: 12/31/2022] Open
Abstract
The relevance of PCSK9 in atherosclerosis progression is demonstrated by the benefits observed in patients that have followed PCSK9-targeted therapies. The impact of these therapies is attributed to the plasma lipid-lowering effect induced when LDLR hepatic expression levels are recovered after the suppression of soluble PCSK9. Different studies show that PCSK9 is involved in other mechanisms that take place at different stages during atherosclerosis development. Indeed, PCSK9 regulates the expression of key receptors expressed in macrophages that contribute to lipid-loading, foam cell formation and atherosclerotic plaque formation. PCSK9 is also a regulator of vascular inflammation and its expression correlates with pro-inflammatory cytokines release, inflammatory cell recruitment and plaque destabilization. Furthermore, anti-PCSK9 approaches have demonstrated that by inhibiting PCSK9 activity, the progression of atherosclerotic disease is diminished. PCSK9 also modulates thrombosis by modifying platelets steady-state, leukocyte recruitment and clot formation. In this review we evaluate recent findings on PCSK9 functions in cardiovascular diseases beyond LDL-cholesterol plasma levels regulation.
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Affiliation(s)
- Aureli Luquero
- Cardiovascular Program ICCC, IR-Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain
| | - Lina Badimon
- Cardiovascular Program ICCC, IR-Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.,Centro de Investigación en Red- Área Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain.,Cardiovascular Research Chair, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Maria Borrell-Pages
- Cardiovascular Program ICCC, IR-Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, Barcelona, Spain.,Centro de Investigación en Red- Área Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain
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48
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Zhou Y, Chen W, Lu M, Wang Y. Association Between Circulating Proprotein Convertase Subtilisin/Kexin Type 9 and Major Adverse Cardiovascular Events, Stroke, and All-Cause Mortality: Systemic Review and Meta-Analysis. Front Cardiovasc Med 2021; 8:617249. [PMID: 33738300 PMCID: PMC7960648 DOI: 10.3389/fcvm.2021.617249] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 02/05/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9), a pivotal protein in low-density lipoprotein cholesterol metabolism, has been validated to be an established target for cardiovascular (CV) risk reduction. Nevertheless, prospective studies concerning the associations between circulating PCSK9 and the risk of CV events and mortality have yielded, so far, inconsistent results. Herein, we conducted a meta-analysis to evaluate the association systemically. Methods: Pertinent studies were identified from PubMed, EMBASE, and Cochrane Library database through July 2020. Longitudinal studies investigating the value of circulating PCSK9 for predicting major adverse cardiovascular events (MACEs) or stroke or all-cause mortally with risk estimates and 95% confidence intervals (CI) were included in the analyses. Dose-response meta-analysis was also applied to evaluate circulating PCSK9 and risk of MACEs in this study. Results: A total of 22 eligible cohorts comprising 28,319 participants from 20 eligible articles were finally included in the study. The pooled relative risk (RR) of MACEs for one standard deviation increase in baseline PCSK9 was 1.120 (95% CI, 1.056-1.189). When categorizing subjects into tertiles, the pooled RR for the highest tertile of baseline PCSK9 was 1.252 (95% CI, 1.104-1.420) compared with the lowest category. This positive association between PCSK9 level and risk of MACEs persisted in sensitivity and most of the subgroup analyses. Twelve studies were included in dose-response meta-analysis, and a linear association between PCSK9 concentration and risk of MACEs was observed (x2 test for non-linearity = 0.31, P non-linearity = 0.575). No significant correlation was found either on stroke or all-cause mortality. Conclusion: This meta-analysis added further evidence that high circulating PCSK9 concentration significantly associated with increased risk of MACEs, and a linear dose-response association was observed. However, available data did not suggest significant association either on stroke or all-cause mortality. Additional well-designed studies are warranted to further investigate the correlations between PCSK9 concentration and stroke and mortality.
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Affiliation(s)
- Yimo Zhou
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
| | - Weiqi Chen
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
| | - Meng Lu
- Department of Pharmacy, National Center of Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongjun Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
- China National Clinical Research Center for Neurological Diseases, Beijing, China
- Center of Stroke, Beijing Institute for Brain Disorders, Beijing, China
- Beijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing, China
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Zeng J, Tao J, Xi L, Wang Z, Liu L. PCSK9 mediates the oxidative low‑density lipoprotein‑induced pyroptosis of vascular endothelial cells via the UQCRC1/ROS pathway. Int J Mol Med 2021; 47:53. [PMID: 33576442 PMCID: PMC7895513 DOI: 10.3892/ijmm.2021.4886] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 01/22/2021] [Indexed: 02/06/2023] Open
Abstract
The present study aimed to explore the role and mechanisms of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the oxidized low-density lipoprotein (oxLDL)-induced pyroptosis of vascular endothelial cells. For this purpose, human umbilical vein endothelial cells (HUVECs) were incubated with oxLDL (100 µg/ml) for 24 h to induce pyroptosis, which was detected using PI/hoechst33342 double staining. The expression of pyroptosis-associated molecules was measured by western blot analysis and RT-qPCR. Reactive oxygen species (ROS) and membrane potential were examined through ROS probe and JC-1 staining, respectively. PCSK9 and mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) protein were knocked down by small interfering RNA (siRNA). PCSK9 was overexpressed by lentivirus. The results revealed that oxLDL induced HUVEC injury, pyroptosis and inflammatory factor release, and upregulated the expression of PCSK9 protein in the HUVECs in a concentration-dependent manner. The silencing of PCSK9 expression with siRNA suppressed the oxLDL-induced damage to HUVECs, the release of inflammatory substances and the occurrence of pyroptosis. In addition, oxLDL inhibited UQCRC1 expression, promoted mitochondrial membrane potential collapse and damaged mitochondrial function; however, these processes were reversed by the silencing of PCSK9. PCSK9 overexpression induced the pyroptosis of HUVECs, the generation of ROS and the disorder of mitochondrial function by inhibiting UQCRC1. Therefore, PCSK9 mediates the oxLDL-induced pyroptosis of vascular endothelial cells via the UQCRC1/ROS pathway.
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Affiliation(s)
- Junfa Zeng
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Jun Tao
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Linzhen Xi
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Zuo Wang
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Lushan Liu
- Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, P.R. China
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50
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Gao H, Guo Z. LncRNA XIST regulates atherosclerosis progression in ox-LDL-induced HUVECs. Open Med (Wars) 2021; 16:117-127. [PMID: 33542956 PMCID: PMC7819546 DOI: 10.1515/med-2021-0200] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 10/24/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) have been verified as vital regulators in human disease, including atherosclerosis. However, the precise role of X-inactive-specific transcript (XIST) in atherosclerosis remains unclear. The proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs) exposed to low-density lipoprotein (ox-LDL) were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazol-3-ium bromide, and flow cytometry assays, correspondingly. The western blot assay was used to quantify protein expression. Lactate dehydrogenase activity and the concentrations of inflammatory factors were measured by matched kits. The real-time quantitative polymerase chain reaction (qPCR) was used to determine α-smooth muscle actin, smooth muscle protein 22-α, XIST, miR-98-5p, and pregnancy-associated plasma protein A (PAPPA) levels in HUVECs. The relationship among XIST, miR-98-5p, and PAPPA was analyzed by dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays. We found ox-LDL repressed proliferation and induced inflammation and apoptosis in HUVECs. Loss-of-functional experiment suggested that the downregulation of XIST overturned the ox-LDL-induced effects on HUVECs. Additionally, overexpression of miR-98-5p-induced effects on ox-LDL-stimulated HUVECs was abolished by upregulation of XIST. However, silencing of miR-98-5p strengthened the ox-LDL-induced effects on HUVECs by increasing expression of PAPPA. Mechanistically, XIST could regulate PAPPA expression in ox-LDL-induced HUVECs by sponging miR-98-5p, providing understanding for atherosclerosis.
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Affiliation(s)
- Hongmei Gao
- Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, 150001, Harbin, Heilongjiang, China
| | - Zhaohui Guo
- Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, No. 37 Yiyuan Street, Nangang District, 150001, Harbin, Heilongjiang, China
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